Literature
A selection of publications on microglia
For all the latest publications on microglia click here
Nature, Science, Cell, and Neuron papers on microglia
APOE4/4 is linked to damaging lipid droplets
in Alzheimer's disease microglia
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JCM, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161.
Abstract
Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
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Mitochondrial complex I activity in microglia sustains neuroinflammation
Peruzzotti-Jametti L, Willis CM, Krzak G, Hamel R, Pirvan L, Ionescu RB, Reisz JA, Prag HA, Garcia-Segura ME, Wu V, Xiang Y, Barlas B, Casey AM, van den Bosch AMR, Nicaise AM, Roth L, Bates GR, Huang H, Prasad P, Vincent AE, Frezza C, Viscomi C, Balmus G, Takats Z, Marioni JC, D'Alessandro A, Murphy MP, Mohorianu I, Pluchino S. Mitochondrial complex I activity in microglia sustains neuroinflammation. Nature. 2024 Apr;628(8006):195-203.
Abstract
Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system.
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Microglia maintain structural integrity during fetal brain morphogenesis
Lawrence AR, Canzi A, Bridlance C, Olivié N, Lansonneur C, Catale C, Pizzamiglio L, Kloeckner B, Silvin A, Munro DAD, Fortoul A, Boido D, Zehani F, Cartonnet H, Viguier S, Oller G, Squarzoni P, Candat A, Helft J, Allet C, Watrin F, Manent JB, Paoletti P, Thieffry D, Cantini L, Pridans C, Priller J, Gélot A, Giacobini P, Ciobanu L, Ginhoux F, Thion MS, Lokmane L, Garel S. Microglia maintain structural integrity during fetal brain morphogenesis. Cell. 2024 Feb 15;187(4):962-980.e19.
Abstract
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.
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Type-I-interferon-responsive microglia shape cortical development and behavior
Escoubas CC, Dorman LC, Nguyen PT, Lagares-Linares C, Nakajo H, Anderson SR, Barron JJ, Wade SD, Cuevas B, Vainchtein ID, Silva NJ, Guajardo R, Xiao Y, Lidsky PV, Wang EY, Rivera BM, Taloma SE, Kim DK, Kaminskaya E, Nakao-Inoue H, Schwer B, Arnold TD, Molofsky AB, Condello C, Andino R, Nowakowski TJ, Molofsky AV. Type-I-interferon-responsive microglia shape cortical development and behavior. Cell. 2024 Apr 11;187(8):1936-1954.e24.
Abstract
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.
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Clearance of β-amyloid and synapses by the optogenetic depolarization of microglia is complement selective
Lv Z, Chen L, Chen P, Peng H, Rong Y, Hong W, Zhou Q, Li N, Li B, Paolicelli RC, Zhan Y.
Clearance of β-amyloid and synapses by the optogenetic depolarization of microglia is complement selective.
Neuron. 2024 Mar 6;112(5):740-754.e7.
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Abstract
Microglia actively monitor the neighboring brain microenvironments and constantly contact synapses with their unique ramified processes. In neurodegenerative diseases, including Alzheimer's disease (AD), microglia undergo morphological and functional alterations. Whether the direct manipulation of microglia can selectively or concurrently modulate synaptic function and the response to disease-associated factors remains elusive. Here, we employ optogenetic methods to stimulate microglia in vitro and in vivo. Membrane depolarization rapidly changes microglia morphology and leads to enhanced phagocytosis. We found that the optogenetic stimulation of microglia can efficiently promote β-amyloid (Aβ) clearance in the brain parenchyma, but it can also enhance synapse elimination. Importantly, the inhibition of C1q selectively prevents synapse loss induced by microglia depolarization but does not affect Aβ clearance. Our data reveal independent microglia-mediated phagocytosis pathways toward Aβ and synapses. Our results also shed light on a synergistic strategy of depolarizing microglia and inhibiting complement functions for the clearance of Aβ while sparing synapses.
iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer
Park DS, Kozaki T, Tiwari SK, Moreira M, Khalilnezhad A, Torta F, Olivié N, Thiam CH, Liani O, Silvin A, Phoo WW, Gao L, Triebl A, Tham WK, Gonçalves L, Kong WT, Raman S, Zhang XM, Dunsmore G, Dutertre CA, Lee S, Ong JM, Balachander A, Khalilnezhad S, Lum J, Duan K, Lim ZM, Tan L, Low I, Utami KH, Yeo XY, Di Tommaso S, Dupuy JW, Varga B, Karadottir RT, Madathummal MC, Bonne I, Malleret B, Binte ZY, Wei Da N, Tan Y, Wong WJ, Zhang J, Chen J, Sobota RM, Howland SW, Ng LG, Saltel F, Castel D, Grill J, Minard V, Albani S, Chan JKY, Thion MS, Jung SY, Wenk MR, Pouladi MA, Pasqualini C, Angeli V, Cexus ONF, Ginhoux F. Nature. 2023 Nov;623(7986):397-405.
Abstract
Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.
An in vivo neuroimmune organoid model to study human microglia phenotypes.
Schafer ST, Mansour AA, Schlachetzki JCM, Pena M, Ghassemzadeh S, Mitchell L, Mar A, Quang D, Stumpf S, Ortiz IS, Lana AJ, Baek C, Zaghal R, Glass CK, Nimmerjahn A, Gage FH. Cell. 2023 May 11;186(10):2111-2126.e20.
Abstract
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
Droplet-based forward genetic screening of astrocyte-microglia cross-talk
Wheeler MA, Clark IC, Lee HG, Li Z, Linnerbauer M, Rone JM, Blain M, Akl CF, Piester G, Giovannoni F, Charabati M, Lee JH, Kye YC, Choi J, Sanmarco LM, Srun L, Chung EN, Flausino LE, Andersen BM, Rothhammer V, Yano H, Illouz T, Zandee SEJ, Daniel C, Artis D, Prinz M, Abate AR, Kuchroo VK, Antel JP, Prat A, Quintana FJ. Science. 2023 Mar 10;379(6636):1023-1030.
Abstract
Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.
IL-4 shapes microglia-dependent pruning of the cerebellum during postnatal development
Guedes JR, Ferreira PA, Costa J, Laranjo M, Pinto MJ, Reis T, Cardoso AM, Lebre C, Casquinha M, Gomes M, Shkatova V, Pereira M, Beltrão N, Hanuscheck N, Greenhalgh AD, Vogelaar CF, Carvalho AL, Zipp F, Cardoso AL, Peça J. Neuron. 2023 Nov 1;111(21):3435-3449.e8.
Abstract
Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations. These animals also show a hyperkinetic and impulsive-like phenotype, reminiscent of attention-deficit hyperactivity disorder (ADHD). These alterations are blocked in Il4rαfl/fl::Cx3cr1-CreER mice, which are deficient in IL-4 receptor signaling in microglia. These findings demonstrate a previously unknown role for IL-4 during a neuroimmune critical period of cerebellar maturation and provide a first putative mechanism for the comorbidity between allergic disease and ADHD observed in humans.
TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4
Gratuze M, Schlachetzki JCM, D'Oliveira Albanus R, Jain N, Novotny B, Brase L, Rodriguez L, Mansel C, Kipnis M, O'Brien S, Pasillas MP, Lee C, Manis M, Colonna M, Harari O, Glass CK, Ulrich JD, Holtzman DM. Neuron. 2023 Jan 18;111(2):202-219.e7.
Abstract
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.
CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord
Sun S, Li J, Wang S, Li J, Ren J, Bao Z, Sun L, Ma X, Zheng F, Ma S, Sun L, Wang M, Yu Y, Ma M, Wang Q, Chen Z, Ma H, Wang X, Wu Z, Zhang H, Yan K, Yang Y, Zhang Y, Zhang S, Lei J, Teng ZQ, Liu CM, Bai G, Wang YJ, Li J, Wang X, Zhao G, Jiang T, Belmonte JCI, Qu J, Zhang W, Liu GH. . Nature. 2023 Dec;624(7992):611-620.
Abstract
Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.
cGAS-STING drives ageing-related inflammation and neurodegeneration
Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, Thacker VV, Favre L, Mangeat B, Kroese LJ, Krimpenfort P, Prinz M, Ablasser A. cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature. 2023 Aug;620(7973):374-380.
Abstract
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy
Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn MB, Hu H, Shchukina I, Kim MW, Yuede CM, Kipnis J, Artyomov MN, Ulrich JD, Holtzman DM. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023 Mar;615(7953):668-677.
Abstract
Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.
Microglia regulate central nervous system myelin growth and integrity
McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J, Miron VE. Nature. 2023 Jan;613(7942):120-129.
Abstract
Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease.
An in vivo neuroimmune organoid model to study human microglia phenotypes
Schafer ST, Mansour AA, Schlachetzki JCM, Pena M, Ghassemzadeh S, Mitchell L, Mar A, Quang D, Stumpf S, Ortiz IS, Lana AJ, Baek C, Zaghal R, Glass CK, Nimmerjahn A, Gage FH. An in vivo neuroimmune organoid model to study human microglia phenotypes. Cell. 2023 May 11;186(10):2111-2126.e20.
Abstract
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
Stratoulias V, Ruiz R, Kanatani S, Osman AM, Keane L, Armengol JA, Rodríguez-Moreno A, Murgoci AN, García-Domínguez I, Alonso-Bellido I, González Ibáñez F, Picard K, Vázquez-Cabrera G, Posada-Pérez M, Vernoux N, Tejera D, Grabert K, Cheray M, González-Rodríguez P, Pérez-Villegas EM, Martínez-Gallego I, Lastra-Romero A, Brodin D, Avila-Cariño J, Cao Y, Airavaara M, Uhlén P, Heneka MT, Tremblay MÈ, Blomgren K, Venero JL, Joseph B. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Nat Neurosci. 2023 Jun;26(6):1008-1020.
Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1-microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry
Hayes LN, An K, Carloni E, Li F, Vincent E, Trippaers C, Paranjpe M, Dölen G, Goff LA, Ramos A, Kano SI, Sawa A. Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry. Nature. 2022 Oct;610(7931):327-334.
Abstract
Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors-such as an aberrant microbiome, immune activation and poor nutrition-can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.
Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes
Shi Z, Yu P, Lin WJ, Chen S, Hu X, Chen S, Cheng J, Liu Q, Yang Y, Li S, Zhang Z, Xie J, Jiang J, He B, Li Y, Li H, Xu Y, Zeng J, Huang J, Mei J, Cai J, Chen J, Wu LJ, Ko H, Tang Y. Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes. Neuron. 2023 Mar 1;111(5):696-710.e9.
Abstract
The crosstalk between the nervous and immune systems has gained increasing attention for its emerging role in neurological diseases. Radiation-induced brain injury (RIBI) remains the most common medical complication of cranial radiotherapy, and its pathological mechanisms have yet to be elucidated. Here, using single-cell RNA and T cell receptor sequencing, we found infiltration and clonal expansion of CD8+ T lymphocytes in the lesioned brain tissues of RIBI patients. Furthermore, by strategies of genetic or pharmacologic interruption, we identified a chemotactic action of microglia-derived CCL2/CCL8 chemokines in mediating the infiltration of CCR2+/CCR5+CD8+ T cells and tissue damage in RIBI mice. Such a chemotactic axis also participated in the progression of cerebral infarction in the mouse model of ischemic injury. Our findings therefore highlight the critical role of microglia in mediating the dysregulation of adaptive immune responses and reveal a potential therapeutic strategy for non-infectious brain diseases.
Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease
Hu J, Chen Q, Zhu H, Hou L, Liu W, Yang Q, Shen H, Chai G, Zhang B, Chen S, Cai Z, Wu C, Hong F, Li H, Chen S, Xiao N, Wang ZX, Zhang X, Wang B, Zhang L, Mo W. Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease. Neuron. 2023 Jan 4;111(1):15-29.e8.
Abstract
The pathology of Alzheimer's disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca2+ influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
Wang S, Sudan R, Peng V, Zhou Y, Du S, Yuede CM, Lei T, Hou J, Cai Z, Cella M, Nguyen K, Poliani PL, Beatty WL, Chen Y, Cao S, Lin K, Rodrigues C, Ellebedy AH, Gilfillan S, Brown GD, Holtzman DM, Brioschi S, Colonna M. TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Cell. 2022 Oct 27;185(22):4153-4169.e19.
Abstract
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47Hvariant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25.
Abstract
The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis
Absinta, M., Maric, D., Gharagozloo, M., Garton, T., Smith, M.D., Jin, J., Fitzgerald, K.C., Song, A., Liu, P., Lin, J.P. and Wu, T., 2021. A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis. Nature, pp.1-6.
Abstract
Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.
Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C
Chu, T.T., Tu, X., Yang, K., Wu, J., Repa, J.J. and Yan, N., 2021. Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C. Nature, 596(7873), pp.570-575.
Abstract
The classic mode of STING activation is through binding the cyclic dinucleotide 2'3'-cyclic GMP-AMP (cGAMP), produced by the DNA sensor cyclic GMP-AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann-Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 'primes' STING signalling by physically linking or 'tethering' STING to SREBP2 trafficking. Loss of NPC1 protein also 'boosts' STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1-/- mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1-/- mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.
Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease
McAlpine, C.S., Park, J., Griciuc, A., Kim, E., Choi, S.H., Iwamoto, Y., Kiss, M.G., Christie, K.A., Vinegoni, C., Poller, W.C. and Mindur, J.E., 2021. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature, 595(7869), pp.701-706.
Abstract
Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.
Dysregulation of brain and choroid plexus cell types in severe COVID-19
Yang, A.C., Kern, F., Losada, P.M., Agam, M.R., Maat, C.A., Schmartz, G.P., Fehlmann, T., Stein, J.A., Schaum, N., Lee, D.P. and Calcuttawala, K., 2021. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 595(7868), pp.565-571.
Abstract
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1-3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4-6. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans7 and linked to cognitive function8-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
Da Mesquita, S., Papadopoulos, Z., Dykstra, T., Brase, L., Farias, F.G., Wall, M., Jiang, H., Kodira, C.D., de Lima, K.A., Herz, J. and Louveau, A., 2021. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature, 593(7858), pp.255-260.
Abstract
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Restoring metabolism of myeloid cells reverses cognitive decline in ageing
Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R., Durairaj, A.S., Wang, Q., Rubin, A., Joshi, A.U., He, J.Q., Gauba, E., Liu, L. and Wang, C., 2021. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature, 590(7844), pp.122-128.
Abstract
Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
Microglia esprit de corps: Sharing the burden of eliminating toxic aggregates
Chen, Y. and Colonna, M., 2021. Microglia esprit de corps: Sharing the burden of eliminating toxic aggregates. Cell, 184(20), pp.5082-5084.
Abstract
Microglia play critical roles in the defense against neurodegenerative diseases. In this issue of Cell, Scheiblich et al. focus on microglia that ingest toxic aggregates of α-synuclein, finding that α-synuclein-replete microglia exchange aggregates for healthy mitochondria via nanotube connections to unaffected microglia. This communication enables a shared approach to aggregates disposal while preserving the health of the microglial population.
Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes
Scheiblich, H., Dansokho, C., Mercan, D., Schmidt, S.V., Bousset, L., Wischhof, L., Eikens, F., Odainic, A., Spitzer, J., Griep, A. and Schwartz, S., 2021. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell.
Abstract
Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic α-syn clearance.
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic
Logan, T., Simon, M.J., Rana, A., Cherf, G.M., Srivastava, A., Davis, S.S., Low, R.L.Y., Chiu, C.L., Fang, M., Huang, F. and Bhalla, A., 2021. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell, 184(18), pp.4651-4668.
Abstract
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.
GABA-receptive microglia selectively sculpt developing inhibitory circuits
Favuzzi, E., Huang, S., Saldi, G.A., Binan, L., Ibrahim, L.A., Fernández-Otero, M., Cao, Y., Zeine, A., Sefah, A., Zheng, K. and Xu, Q., 2021. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell, 184(15), pp.4048-4063.
Abstract
Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.
Impact of neurodegenerative diseases on human adult hippocampal neurogenesis
Terreros-Roncal, J., Moreno-Jiménez, E.P., Flor-García, M., Rodríguez-Moreno, C.B., Trinchero, M.F., Cafini, F., Rábano, A. and Llorens-Martín, M., 2021. Impact of neurodegenerative diseases on human adult hippocampal neurogenesis. Science, 374(6571), pp.1106-1113.
Abstract
Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.
Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury
Holden, S.S., Grandi, F.C., Aboubakr, O., Higashikubo, B., Cho, F.S., Chang, A.H., Forero, A.O., Morningstar, A.R., Mathur, V., Kuhn, L.J. and Suri, P., 2021. Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science, 373(6560).
Abstract
Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.
Barcoded viral tracing of single-cell interactions in central nervous system inflammation
Clark, I.C., Gutiérrez-Vázquez, C., Wheeler, M.A., Li, Z., Rothhammer, V., Linnerbauer, M., Sanmarco, L.M., Guo, L., Blain, M., Zandee, S.E. and Chao, C.C., 2021. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science, 372(6540).
Abstract
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
2020 Nature, Science, and Cell papers on microglia
Negative feedback control of neuronal activity by microglia
Badimon, A., Strasburger, H.J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A.T., Graves, S.M., Uweru, J.O. and Ledderose, C., 2020. Negative feedback control of neuronal activity by microglia. Nature, 586(7829), pp.417-423.
Abstract
Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency
Zhang, J., Velmeshev, D., Hashimoto, K., Huang, Y.H., Hofmann, J.W., Shi, X., Chen, J., Leidal, A.M., Dishart, J.G., Cahill, M.K. and Kelley, K.W., 2020. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature, pp.1-7.
Abstract
Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn−/− microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn−/− microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.
Microglia-organized scar-free spinal cord repair in neonatal mice
Li, Y., He, X., Kawaguchi, R., Zhang, Y., Wang, Q., Monavarfeshani, A., Yang, Z., Chen, B., Shi, Z., Meng, H. and Zhou, S., 2020. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature, pp.1-6.
Abstract
Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons1,2,3,4. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal—but not adult—microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
Microglia monitor and protect neuronal function through specialized somatic purinergic junctions
Cserép, C., Pósfai, B., Lénárt, N., Fekete, R., László, Z.I., Lele, Z., Orsolits, B., Molnár, G., Heindl, S., Schwarcz, A.D. and Ujvári, K., 2020. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science, 367(6477), pp.528-537.
Abstract
Microglia are the main immune cells in the brain and have roles in brain homeostasis and neurological diseases. Mechanisms underlying microglia–neuron communication remain elusive. Here, we identified an interaction site between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia–neuron junctions have a specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria was linked with microglial junction formation, which was induced rapidly in response to neuronal activation and blocked by inhibition of P2Y12 receptors. Brain injury–induced changes at somatic junctions triggered P2Y12 receptor–dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Thus, microglial processes at these junctions could potentially monitor and protect neuronal functions.
Microglia mediate forgetting via complement-dependent synaptic elimination
Wang, C., Yue, H., Hu, Z., Shen, Y., Ma, J., Li, J., Wang, X.D., Wang, L., Sun, B., Shi, P. and Wang, L., 2020. Microglia mediate forgetting via complement-dependent synaptic elimination. Science, 367(6478), pp.688-694.
Abstract
Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.
Human fetal microglia acquire homeostatic immune-sensing properties early in development
Kracht, L., Borggrewe, M., Eskandar, S., Brouwer, N., de Sousa Lopes, S.C., Laman, J.D., Scherjon, S.A., Prins, J.R., Kooistra, S.M. and Eggen, B.J.L., 2020. Human fetal microglia acquire homeostatic immune-sensing properties early in development. Science, 369(6503), pp.530-537.
Abstract
Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this developmental period and increasingly resemble adult microglia with CNS-surveilling properties. Chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. Thus, during early fetal development, microglia progress toward a more mature, immune-sensing competent phenotype, and this might render the developing human CNS vulnerable to environmental perturbations during early pregnancy.
Restoring metabolism of myeloid cells reverses cognitive decline in ageing
Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R., Durairaj, A.S., Wang, Q., Rubin, A., Joshi, A.U., He, J.Q., Gauba, E., Liu, L. and Wang, C., 2021. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature, pp.1-7.
Abstract
Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1,2,3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease4,5,6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases
Bartels, T., De Schepper, S. and Hong, S., 2020. Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases. Science, 370(6512), pp.66-69.
Abstract
Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer’s and Parkinson’s diseases. Understanding how to assess and modulate microglia-neuron interactions critical for brain health will be key to developing effective therapies for dementia.
Brain cell type–specific enhancer–promoter interactome maps and disease-risk association
Nott, A., Holtman, I.R., Coufal, N.G., Schlachetzki, J.C., Yu, M., Hu, R., Han, C.Z., Pena, M., Xiao, J., Wu, Y. and Keulen, Z., 2019. Brain cell type–specific enhancer–promoter interactome maps and disease-risk association. Science, 366(6469), pp.1134-1139.
Abstract
Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.
Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia
Ndoja, A., Reja, R., Lee, S.H., Webster, J.D., Ngu, H., Rose, C.M., Kirkpatrick, D.S., Modrusan, Z., Chen, Y.J.J., Dugger, D.L. and Gandham, V., 2020. Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia. Cell, 182(5), pp.1156-1169.
Abstract
Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer’s disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPβ) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPβ-dependent gene expression programs in microglia.
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Pasciuto, E., Burton, O.T., Roca, C.P., Lagou, V., Rajan, W.D., Theys, T., Mancuso, R., Tito, R.Y., Kouser, L., Callaerts-Vegh, Z. and Alerie, G., 2020. Microglia require CD4 T cells to complete the fetal-to-adult transition. Cell, 182(3), pp.625-640.
Abstract
The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems.
Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Nguyen, P.T., Dorman, L.C., Pan, S., Vainchtein, I.D., Han, R.T., Nakao-Inoue, H., Taloma, S.E., Barron, J.J., Molofsky, A.B., Kheirbek, M.A. and Molofsky, A.V., 2020. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell, 182(2), pp.388-403.
Abstract
Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.
Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development
Utz, S.G., See, P., Mildenberger, W., Thion, M.S., Silvin, A., Lutz, M., Ingelfinger, F., Rayan, N.A., Lelios, I., Buttgereit, A. and Asano, K., 2020. Early fate defines microglia and non-parenchymal brain macrophage development. Cell, 181(3), pp.557-573.
Abstract
Central nervous system (CNS) macrophages comprise microglia and border-associated macrophages (BAMs) residing in the meninges, the choroid plexus, and the perivascular spaces. Most CNS macrophages emerge during development, with the exception of choroid plexus and dural macrophages, which are replaced by monocytes in adulthood. Whether microglia and BAMs share a developmental program or arise from separate lineages remains unknown. Here, we identified two phenotypically, transcriptionally, and locally distinct brain macrophages throughout development, giving rise to either microglia or BAMs. Two macrophage populations were already present in the yolk sac suggesting an early segregation. Fate-mapping models revealed that BAMs mostly derived from early erythro-myeloid progenitors in the yolk sac. The development of microglia was dependent on TGF-β, whereas the genesis of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene signature, and requirement for TGF-β.
Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner
Willis, E.F., MacDonald, K.P., Nguyen, Q.H., Garrido, A.L., Gillespie, E.R., Harley, S.B., Bartlett, P.F., Schroder, W.A., Yates, A.G., Anthony, D.C. and Rose-John, S., 2020. Repopulating microglia promote brain repair in an IL-6-dependent manner. Cell, 180(5), pp.833-846.
Abstract
Cognitive dysfunction and reactive microglia are hallmarks of traumatic brain injury (TBI), yet whether these cells contribute to cognitive deficits and secondary inflammatory pathology remains poorly understood. Here, we show that removal of microglia from the mouse brain has little effect on the outcome of TBI, but inducing the turnover of these cells through either pharmacologic or genetic approaches can yield a neuroprotective microglial phenotype that profoundly aids recovery. The beneficial effects of these repopulating microglia are critically dependent on interleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) and robustly support adult neurogenesis, specifically by augmenting the survival of newborn neurons that directly support cognitive function. We conclude that microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.