Introduction
Viral encephalitis
Relevance of murine models to human viral encephalitis disease
Microglia in viral encephalitis
Neuroprotective role of microglia in acute-phase viral encephalitis
Study | Virus | Infection | # days mice were fed PLX5622 before infection | Mice | Enhanced mortality? | Enhanced morbidity? | Enhanced weight loss? | Enhanced viral load? |
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Sanchez et al. [274] | Daniel's strain of TMEV | intracranial (i.c) | 7 | C57BL/6 Males 4 weeks old | Yes | Yes | Not recorded (N/R) | N/R |
Funk et al. [107] | WNV-NY, strain 3000.0259 | footpad (f.p) | 14 | C57BL/6 Males 6 weeks old | Yes | Yes | Yes | Yes |
i.c | No | N/R | No | No | ||||
Attenuated WNV-NS5- E218A | Yes | N/R | Yes | Yes | ||||
Wheeler et al. [344] | Neuroattenuated variant of the JHMV strain of MHV | i.c | 7 | C57BL/6 Males 5–6 weeks old | Yes | N/R | N/R | Yes |
N1347A, an rJ macrodomain point mutant virus | intranasal (i.n) | Yes | N/R | N/R | N/R | |||
Recombinant parental JHMV | i.p | Yes | N/R | N/R | N/R | |||
Waltl et al. [334] | Daniel’s strain of TMEV | i.c | 21 | JAX® C57BL/6 J (B6) Female 4 weeks old | Yes | Yes | Yes | Yes |
Seitz et al. [279] | WNV-NY99 | f.p | 14 | Swiss-Webster Female 7–10 weeks old | Yes | N/R | No | Yes |
p3 strain of JEV | Yes | N/R | No | Yes | ||||
Fekete et al. [96] | PRV-Bartha derivative, PRV-Bartha-Dup-Green | intraperitoneal (i.p.) or directly into the epididymal white adipose tissue | 21 | C57BL/6 J Gender not specified 12–18 weeks old | N/R | Yes | N/R | Yes |
Study | Sanchez et al. [274] | Funk et al. [107] | Wheeler et al. [344] | Waltl et al. [334] | Seitz et al. [279] | Fekete et al. [96] | ||||
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Virus | Daniel’s strain of TMEV | WNV-NY, strain 3000.0259 | Attenuated WNV-NS5- E218A | Neuro-attenuated variant of the JHMV strain of MHV | N1347A, an rJ macrodomain point mutant virus | Recombinant parental JHMV (rJHMV) | Daniel’s strain of TMEV | WNV-NY99 | p3 strain of JEV | PRV-Bartha derivative, PRV-Bartha-Dup-Green (BDG) |
Enhanced neuroinflammation/ neurodegeneration? | Axonal damage and demyelination in spinal cords | N/R | Increased neuronal apoptosis in the hippocampus and cerebellum at dpi 6. | N/R | Increased: neuroinflammation, perivascular infiltrates, astrogliosis and neurodegeneration. | N/R | N/R | |||
Change in macrophage infiltrate in PLX5622-treated animals? | N/R | N/R | Decreased numbers of macrophages Reduced CD86 expression. | Increased numbers of macrophages. Reduced expression of MHC-II, increased expression of Ly6C and differential expression of 235 genes. | N/R | No change | N/R | Decreased numbers of macrophages. | ||
Change in cytokine production in the CNS of PLX562- treated animals? | N/R | N/R | Decreased RNA: IFN-β, IFN-γ, TNF, NOS2, CD86 & CD68 (brain). | Increased RNA: IFN-β, IL6 at dpi 3 and IFN-α, IFN-β, IL6 at dpi 5. No change in protein: IFN-α, IFN-β & IL6 at dpi 5 (brain). | N/R | Decreased RNA: TGF-β1 (brain). Increased RNA: IL-6 (brain), IL10 (brain) & IFN-γ (brain & spinal cord). | Increased RNA: CCL2 at dpi 6 and CCL2, CCL7, CXCL9 & CXCL10 at dpi 9 (brain). | Increased RNA: CCL3 at dpi 8 (brain). | Decreased protein: IL-1α & RANTES (hypothalamic brain tissue). | |
Altered T cell response in the CNS in PLX5622-treated animals? | N/R | N/R | Increased percentage and number of CD8+ T cells. CD8+CD45+NS4B+ T cells showed a decreased frequency of CD69+ and CD160+ cells and reduced expression of CD69 and CD160. All relative to infected, non-microglia-depleted animals. | Decreased percentage & numbers of CD4+ T cells & virus-specific CD4+ T cells. Decreased percentage & numbers T regs. All relative to infected, non-microglia-depleted animals. | N/R | Increased T regs in the spinal cord and hippocampus (relative to microglia-depleted, non-infected animals). Decreased numbers CD4+ and CD4+CD44+ T cells in the whole brain (relative to non-depleted, infected animals). | N/R | No change in the number of CD8+CD3+ T cells in the brain (relative to non-depleted and/or infected animals). | ||
Systemic responses in PLX5622-treated animals | N/R | Loss of CD80 (percentage & numbers) & CD86 (percentage & mean fluorescence intensity) expression on MHC-II+CD11c+CD45+ (DCs) cells, increase in the numbers of CD4+ and CD8+ T cells, no change in CD69+ on CD8+ CD45+ T cells and no change in WNV-specific NS4B+ tetramer staining of CD8+CD45+ cells in the spleen of WNV-NS5- E218A infected, PLX5622-treated animals Decreased CD80 expression on DCs in the blood and decreased CD86 on DCs pDLN at dpi 4 (WNV-NY, f.p.) Reduced numbers of CD45+MHC-II+CD11c+ and CD11b-CD11c+ in the blood in non-infected, PLX-treated animals No change in antigen-presenting cell (APC) populations in the spleen or BM in non-infected, PLX5622-treated animals No changes in T cells, CD11b+, Ly6C+ or Ly6G+ cells in spleen, BM or blood in non-infected, PLX5622-treated animals | No change in the number of CD11b+ cells in the non-infected spleen No change in the total number of cells on dpi 3 or 5 in the draining cervical lymph nodes (dCLN) in i.c. MHV-infection PLX5622 treatment did not change the number of virus-specific CD4+ or CD8+ T cells after i.p. infection with rJ | Reduced number of CSF1R monocytes in the blood in PLX5622-treated mock and infected groups compared to non-PLX-treated animals No change CD4+ and CD8+ ratio in the spleen of PLX5622-treated animals No change in the number Iba1+ macrophages in the spleen (by immunohistochemistry) | N/R | PLX5622 did not cause a significant reduction in circulating or splenic myeloid populations: monocytes, granulocytes, macrophages and B cells Increase in circulating granulocytes (non-significant – infected depleted vs infected non-depleted, significant – infected depleted vs non-infected depleted) Decrease in circulating CD8+ T cells (non-significant – infected depleted vs infected non-depleted, significant – infected depleted vs non-infected depleted) | ||||
Protective role of microglia | Microglia mediate antiviral responses in the CNS | Microglia are important in the restimulation of a CD8+ T cell in the CNS for an effective antiviral T cell response to control viral spread Lack of virologic control was specifically due to the reduction in APCs (as measured by macrophage and microglial expression of B7 molecules) in the CNS, important for a CD8+ T cell response | Microglia are important in the earliest stages of disease, preventing the neurological spread of the virus by restimulating CD4+ T cells that enter the brain The absence of microglia was associated with the infiltration of immature macrophages and the reduction in MHC-II in the CNS (on microglia and macrophages), preventing the local reactivation of CD4+ T cells for an effective antiviral T cell response | Microglia depletion resulted in increased numbers of T regs and IL-10, suppressing cytotoxic CD8+ T cell activity and preventing an effective antiviral T cell response to control viral spread | Microglia mediate antiviral responses in the CNS | The protective role of microglia relies on the rapid and precise migration of microglia to virally infected neurons and the subsequent phagocytosis to prevent viral spread and the presence of viral antigens in the brain |
Microglial role in effective T cell responses mediating viral clearance
CD8+ T cells
CD4+ T cells
T regulatory cells
The role of microglia in MDM maturation and CNS infiltration
The role of microglial migration and phagocytosis in virus control
Role of aberrant synaptic pruning in post-viral cognitive dysfunction
Monocytes in viral encephalitis
Microglia | Monocyte-derived cells | |
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RNA | CD45lo/intCD11b+ microglia ↑ 'microglia-specific' genes relative to macrophages: Bmpr1a, Il12b, Gas6, Tnf, Cd74, Ccl12, Csf1, Ly86, Bst2, H2-Aa, H2-Ab1, Ifnb1, Stat1, Tlr2 and Tlr3 (among many others) ↑ reactive ‘microglia-specific’ genes relative to homeostatic microglia: Itgal, Il12rb1 and Ccl5 (TMEV infection, dpi 6, bulk RNA-seq [78]) | CD45hiCD11b+ macrophages ↑ ‘macrophage-specific’ genes relative to microglia: Gzmb, Il2ra, Nos2, Oas3, Ms4a8a, Arg2, Trem-1, Ly6c2, Ccr2, Vim, Ifi204, S100a10 and Msrb1 (TMEV infection, dpi 6, bulk RNA-seq [78]) |
Protein | CD45lo/intCD11b+ microglia ↑ CD45 and MHC-II (TMEV infection, dpi 6, flow cytometry [78]) | CD45hiCD11b+ macrophages ↑ MHC-II (TMEV infection, dpi 6, flow cytometry [78]) |
CD45intCD11b+Ly6Clo microglia ↑ CD45 and Ly6C (Sarafend strain, WNV infection, dpi 7, flow cytometry [123]) | Bead+CD45intCD11b+ macrophages ↓Ly6C ↑ MHC-II and CD86 (Sarafend strain, WNV infection, dpi 7, flow cytometry [123]) | |
CD45+Iba-1+CD68+P2RY12+ microglia ↑ P2RY12 and CD45 (PRV-infection, dpi 5–7, immunohistochemistry [96]) | ||
Four microglia populations in the homeostatic and WNV-infected brain All differentially express: CD45, CD11b, CX3CR1, F4/80, P2RY12, TMEM119, CD64, MerTK and CD68 Phenotype 1: P2RY12hi CD86+ Phenotype 2: P2RY12lo CD86+ Phenotype 3: P2RY12hi CD86− Phenotype 4: P2RY12lo CD86− Relative to mock-infected mice, the total microglial population in the WNV-infected brain at dpi 7: ↑↑ CD45 and CD64 ↑ CD86 and CD11c ↓↓ CX3CR1, F4/80, TMEM119 and CD68; ↓ P2RY12 (WNV infection at dpi 7, spectral and conventional flow cytometry [298]) | ||
Neuro-protective roles | Microglia re-stimulate CD8+ T cells [107] and CD4+ T cells [344] in the CNS during WNV and MHV infection, respectively, for an effective antiviral T cell response Microglia are required in the earlier stages of MHV infection and their absence is associated with the infiltration of immature antigen-presenting macrophages in the CNS [344] Microglia regulate the infiltration of Tregs and their expression of IL-10 in the CNS of TMEV-infected animals, to prevent the suppression of cytotoxic CD8+ T cell activity [335] Microglia rapidly migrate to and phagocytose PRV-infected neurons to prevent viral spread in the brain [96] Microglia accumulate in the olfactory bulb and form an innate immune barrier to prevent the spread of VSV to caudal parts of the brain [59] Microglia prevent the fatal spread of VSV by acquiring viral antigen from VSV-infected neurons and cross-presenting it to CD8+ T cells via MHC-I [234] | CCL2- and CCL7-dependent monocyte migration to the brain is required for effective viral clearance and survival in WNV encephalitis (neurotropic WNV) [16] CNS-infiltrating macrophages prevent viremia and enhance survival in WNV encephalitis (neurotropic WNV) [22] |
Neuro- toxic roles | IFN-γ signalling in microglia results in neuronal loss and/or synapse elimination during the recovery of WNV and ZIKV infection causing flavivirus-induced hippocampal damage and memory and learning deficits [111] | CNS-infiltrating Ly6Chi monocytes and macrophages contribute to seizure incidence, seizure severity, memory deficits or hippocampal neuron damage in TMEV-induced encephalitis [70, 155, 334] IL-6-producing CD45hiCD11b+ myeloid cells correlate with seizure development in TMEV encephalitis [70, 79] Ly6C+ MDM trafficking into the brain correlates with morality in WNV encephalitis (Sarafend strain) [122, 123] Infiltration of NO-producing Ly6C+ MDM into the CNS correlates with mortality in lethal WNV encephalitis (Sarafend strain) [122] |
Monocyte-mediated viral clearance contributes to secondary tissue damage
Potential role of monocytes in seizure development
Ischemic injury and repair
Relevance of murine models to human ischemic stroke
Microglia in stroke
Microglial modulation of dysfunctional CNS cellular responses in stroke
Microglia | Monocyte-derived cells | |
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RNA | Cxcr4-GFP−CD11b+CD45lo microglia ↑ Siglech, Cx3cr1 and C1qb (‘microglia-specific’ genes) ↑ Plxna4, P2ry12 and P2ry13 (cell surface receptor) ↑ Gpr34, Gpr56, Gpr84 and Adrb2 (heptahelical receptors) ↑ Tlr3 and Tmem173 (pattern recognition receptors) ↑ Mki67 (proliferation marker) (PT, bulk RNA-seq [343]) | Cxcr4-GFP+CD45hiCD11b+Ly6Chi MDM ↑ Siglech, Cx3cr1 and C1q (‘microglia-specific’ genes) ↑ Cybb and the Src kinase Fgr (super-oxide-generating) ↑ Tlr8, Ifi202, Clec7a, Clec4d and Oas2 (pattern recognition molecules) ↑ C3, Cfb and Cfp (complement system components) ↑ H2-Aa, H2-Ab1 and CD74 (antigen processing and presentation via MHC-II) ↑ Irf7, Ifi200b, Ifi202, Ifitm2, Ifitm3, Oas2, Oasl2, Rsad2, Trim25 and Tlr8 (interferon-related genes) ↑ Ccr1, Ccr2, Cxcr4, Plxna1, Plxnc1, Plxnd1, Adgre5, Gpr35, Gpr65 and Gpr132 (cell surface receptors) ↑ Thbs1, Emp1, Ifi207 and Dab (Other genes) (PT, bulk RNA-seq [343]) |
Protein | CD45intCD11b+Ly6C− microglia (tMCAO, flow cytometry [269]) | CD45hiCD11b+Ly6C+Ly6G− monocytes (tMCAO, flow cytometry [269]) |
CD45loCD11b+Ly6C− microglia (PT and tMCAO, flow cytometry [343]) | Cxcr4-GFP+CD45hiCD11b+Ly6Chi Ly6Chi monocytes/MDM (PT and tMCAO, flow cytometry [343]) | |
Cxcr4-GFP+Iba1+TMEM119+ microglia (tMCAO, immunohistochemistry [343]) | CD45hiCD11b+Ly6CloCX3CR1int MDM ↑ CX3CR1, CD206 and Dectin-1 ↓ Ly6C (tMCAO, flow cytometry [339]) | |
CD45+CD11b+TMEM119+ microglia (tMCAO, flow cytometry [168]) | ||
Neuro-protective roles | Microglia sense alterations in neuronal calcium levels, migrating to neurons in infarct regions high in calcium and forming contact interactions to reduce excitotoxic injury [117] | Ly6Chi monocyte infiltration correlated with the expression of anti-inflammatory genes TFG-β, CD163 and Ym1 and are required for long-term functional recovery from stroke [339] Depletion of Ly6ChiCCR2+ monocytes worsened functional outcomes and increased infarct volume 24 h post-stroke [60] Ly6Chi monocyte infiltration prevents hemorrhagic infarct transformation and correlates with tissue expression of collagen-4, TGF-β1 and thrombospondin-1 genes, implicating a role for BBB maintenance following ischemic injury [127] |
Microglia in the periphery of infarcts phagocytose infiltrating neutrophils to prevent their accumulation. Neutrophils can induce bystander tissue damage which enhances ischemic lesion size and brain injury [248] | ||
Microglia inhibit dysfunctional astrocyte responses by reducing their expression of pro-inflammatory mediators [172] | ||
Neuro-toxic roles | Microglia depletion in diabetic animals with MCAO decreases brain injury and improves survival and cognition, which was associated with preserved working memory, increased myelination in the white matter and reduced inflammatory macrophage infiltration into the CNS [168] |
RNA | Three microglia phenotypes. All express: Hexb and Cst3 ‘Homeostatic’ phenotype: Cx3cr1, P2ry12, Tmem119, Hexb, Cst3, Cx3cr1, Ctsd, Csf1r, Ctss, Sparc, Tmsb4x, P2ry12, P2ry13, C1qa and C1qb TREM-2-independent, ‘intermediate state’ microglia phenotype: ↑ Tyrobp, Apoe, B2m, Ctsd, Ctsb, Fth1 and Lyz2 ↓Cx3cr1, P2ry12, P2ry13 and Tmem119 TREM-2 dependent, damage-associated microglia (DAM) phenotype: ↑↑ Tyrobp, Apoe, B2m, Ctsd, Ctsb, Fth1 and Lyz2 ↑Cst7, Lpl, Trem2, Axl, Cstsl, Cd9, Csf1, Ccl6, Itgax, Clec7a, Lilrb4 and Timp2 ↓↓ Cx3cr1, P2ry12, P2ry13 and Tmem119 (5xFAD at 3 and 8 months, single-cell RNA-seq [179]) |
Microglia neurodegenerative phenotype (MGnD) ↓↓ P2ry12, Tmem119, Gpr34, Jun, Olfml3, Csf1r, Hexb, Mertk, Rhob, Cx3cr1, Tgfbr1, Tgfb1, Mef2a, Mafb, Jun, Sall1 and Egr1 (‘homeostatic’ genes) ↑ Spp1, Itgax, Axl, Lilrb4, Clec7a, Ccl2, Csf1 and Apoe (‘inflammatory’ genes) (APP-PS1 at 7, 10 and 17 months. MGnD is also seen in ALS (SOD1G93A mice) and in MS (acute EAE), single-cell RNA-seq [191]) | |
Protein | Three microglia phenotypes: Phenotype 1: Clec7a−P2ry12+ (not associated with Aβ plaques) Phenotype 2: Clec7aloP2ry12lo (in close proximity to Aβ plaques) Phenotype 3: Clec7a+P2ry12– Transition from Clec7a− to Clec7aint to Clec7ahi correlated with increased mRNA expression of Apoe and suppression of homeostatic molecules (APP-PS1, immunohistochemistry [191]) |
Three FCRLS+CD11b+ microglia phenotypes: Phenotype 1: Clec7a− Phenotype 2: Clec7aint Phenotype 3: Clec7a+ (APP-PS1, flow cytometry [191]) | |
Iba-1+CD11c+TIMP2+ microglia Co-localized with Aβ+, Csf1 and Lpl (5xFAD, immunohistochemistry & smFISHa [179]) | |
Neuro- protective roles | Microglia encircle Aβ plaques to prevent further growth and dissemination into the parenchyma [63], reducing damage to local neurites [295] Microglia may contribute to the phagocytic and enzymatic clearance of the Aβ plaque deposits [82] TREM2 expressed by damage-associated microglia is thought to directly recognise Aβ to enhance engulfment and lysosomal degradation of the protein [338, 357, 366] TREM2-dependent microglia functions are required to prevent seeding of plaques earlier in AD, whilst later on enhance the consolidation of Aβ into highly compact plaques [222] |
Neuro- toxic roles |
Microglia | Monocyte-derived cells | |
---|---|---|
RNA | FCRLS+ CD11b+ microglia All express: ↓↓ P2ry12, Tmem119, Tgfbr1, Mafb, Mef2a, Sall1 and Egr1 (homeostatic genes) ↑ Apoe (pro-inflammatory molecule) Downregulated/upregulated genes in acute phase of EAE were restored to homeostatic levels during recovery phase (acute EAE, single-cell RNA-seq [191]) | Ly6ChiCD11c+MHC-II+CD11b+CD45hi MoDC All express: GM-CSF-dependent gene signature: ↑ CCL6, CCL17, CCL24 and Tnfrsf9 (co-stimulatory molecules) ↑ Mfge8, Cd1d1, Pld1, Scarb1, Clec7a and Anxa1 (phagocytosis-associated genes) ↑ Asc, NLRP3, and Pycard (inflammasome-associated genes) (peak EAE, next-generation sequencing [67]) |
Four disease-associated microglia (daMG) phenotypes. All express: Bhlhe41lo, Gpr34lo, Hexb, Olfml3, P2ry13, Sall1lo, Serpine2lo, Siglechlo, Sparc+, Maflo, Slc2a5lo, Ccl2hi, Cxcl10hi, Ly86hi, Mki67+, Selplglo, Cx3cr1lo, Fcr1lo, Csfr, Csf1, C1qc, C1qb and C1qa daMG 1: Cd83hi, Ctsdhi, Cd8hi, P2ry12+ and TMEM119+ daMG 2: Cd83hi, Ctsdhi, Cd8hi, P2ry12+ and TMEM119+ (not found in lesions) daMG 3: Ctsbhi, Apoehi, B2mhi, Cst7hi, Mpeg1hi, CD74hi, Cxcl10lo, P2ry12lo and TMEM119lo (more likely to make contact with T cells) daMG 4: Itm2bhi, Ctsshi, Ccl5hi, Naaahi, CD74lo, P2ry12lo and TMEM119lo (daMG 3 and 4 have the highest proliferative capacity) (peak EAE, single-cell RNA-seq [174]) | Four monocyte-derived cell populations in the parenchyma and perivascular space. All express: Ly6c2, Ccr2, Cd44 and Fcgr1 Ly6Chi monocytes: Fn1 MertK+ MDM subset 1: Fn1 and Mertk MerTK+ MDM subset 2 and 3: Fn1, Mertk, Mrc1 and Ms4a7 MoDC: Fn1, Kmo and Zbtb46 (peak EAE, single-cell RNA-seq [174]) | |
Three microglia (Mg) populations. All express: P2ry12, Tmem119, Cx3cr1, Hexb and Olfml3 Top 10 DEGa and top GOb terms associated with each population: Mg III: Cd74, Ifi27l2a, Cst7, Fcgr4, Lgals3bp, Cxcl10, Iigp1, H2-K1, H2-D1 and Fgl2 (antigen processing and presentation) Mg IV: Stmn1, Top2a, Hmgb2, Ube2c, 2810417H13Rik, Birc5, Cks1b, Spp1, Ifi27l2a and Ccl12 (cell division) Mg V: AA467197, Lgals3, Lyz2, Arg1, AW112010, Plac8, Cxcl2, Ccl5, Il1b and Tgfbi (ROS metabolic process) Also expressed the ‘oxidative stress’ signature Cybb, Ncf2, Ncf4 and Gpx1 (onset EAE, Toxic single-cell RNA-seq [224]) | Seven monocyte populations: All express: Ly6Chi monocytes: Ly6c2, Sell and Ccr2 Ly6Clo monocytes: Nr4a1 and Pparg Ifit2+ monocytes: Ifit1, Ifit2, Ifit3, Usp18 and Irf7 Arg1+ macrophages: Arg1, Apoc2 and C1qb Nos2+ macrophages: Nos2, Gpnmb, Arg1and Fabp5 Saa3+ monocytes: Saa3, Plac8 and Gbp2 Cxcl10+ monocytes: Cxcl9, Cxcl10 and Il1b (peak and chronic EAE, MARS-seq [124]) | |
Seven monocyte/macrophage (Mp) populations: All express: Top 10 DEGa and top GOb terms associated with each populationL Mp I: Clec4n, Inhba, Cd9, Ccl6, Clec7a, Cfb, Bcl2a1d, Il1a, Nos2 and Arg1 (ROS metabolic process) Mp II: Cd81, Sparc, Ccl12, C1qa, C1qc, Hexb, Cx3cr1, Ly86, Olfml3 and Cd63 (inflammatory response) Mp III: Apoe, C1qc, C1qa, C1qb, Apoc2, Trem2, Ccl5, Ms4a7, H2-Eb1 and H2-Aa (antigen processing and presentation via MHC-II) Mp IV: Apoe, C1qa, Ms4a7, C1qb, C1qc, Lgmn, Cx3cr1, Ccl12, Ly86 and Trem2 (lipid catabolic process) Mp V: Plac8, Isg15, Gbp2, Ms4a4c, Ifitm1, Ccr2, Tgm2, Actb, Fgl2 and Ifit3 (response to interferon-β) Mp VI: Cxcl10, Ifitm6, S100a4, Lrg1, Ifi203, Gm9733, Ifitm2, Tspan13, Wfdc17 and Tmem176b (cytokine production) Mp VII: S100a9, S100a8, Ngp, Camp, Retnlg, Lcn2, 1100001G20Rik, Ltf, Ifitm6 and Pglyrp1 (leukocyte migration) (onset EAE, Toxic single-cell RNA-seq [224]) | ||
Protein | Three microglia populations. All express: CD45+CD11b+CD317+CD88+MHCI+MerTK+4D4+FCRLS+ Population A: MHC-II−CD39loCD86− (also found in homeostatic brain) Population B: MHC-II−CD39hiCD86+CD80+TIM4+ CCR5+CCR4+ CD206loTREM2lo (also found in homeostatic brain) Population C: MHCII+CD39hiCD86+CD80+Axl+ TIM4+PD-L1+ CD11c+CCR5+CD206loTREM2lo (arises during EAE & Huntington’s Disease) (onset and peak EAE, CyTOF [4]) | Five monocyte-derived cell subsets. All express: CD45+CD11b+Ly6C+ Subset D: PD-L1+MHC-II+AxlhiMerTKintTREM2int CD86hiCD80hiCD206loCD39hiCD38hi Subset E: PD-L1+MHCII+AxlhiMerTKint TREM2intCD86hiCD80hiCD206loCD39hiCD38hi Subset F: PD-L1−CD88−IL-17R−Axl−MerTK−TREM2−CD86intCD80−CD206−CD39intCD38lo Subset G: PD-L1−CD88+IL-17R−Axl−MerTK− TREM2loCD86loCD80loCD206−CD39loCD38int Subset H: PD-L1−CD88+IL-17R+AxlloMerTKlo TREM2loCD86intCD80loCD206loCD39intCD38int (pre-symptomatic, peak, recovery and chronic EAE, CyTOF [4]) |
Three microglia populations. All express: CD45+CD11b+CD317+CD88+MHCI+MerTK+4D4+FCRLS+ Population A: MHC-II−CD39loCD86− Population B: MHC-II−CD39hiCD86+CD80+Ax1+TIM4+ CCR5+CD206loTREM2lo Population C: MHC-II+CD39hiCD86+CD80+Axl+ TIM4+PD-L1+ CD11c+CCR5+CD206loTREM2lo (chronic and recovered EAE, CyTOF [4]) | Two monocyte-derived cell (MC) subsets All express: MerTK+ MC: MerTK+CD64+Ly6C+CD44+ CD209+ MC: CD209+CD64+Ly6C+CD44− (peak EAE, flow cytometry [174]) | |
Four disease-associated microglia (daMG) populations. All express: Iba-1+SPARC+Ly86+CD162+ daMG1: MD-1−P2RY12+TMEM119+ (not localized in lesions) daMG2: MD-1+P2RY12loTMEM119loCD74+ daMG3: MD-1+P2RY12loTMEM119loCXCL10+ daMG4: MD-1+P2RY12loTMEM119loCCL5+ –daMG 2–4 were found localized in lesions (peak EAE, immunohistochemistry [174]) | CD45hiCD11b+F4/80+ macrophages All express: Upregulation of MHC class II (JHMV-induced demyelination, flow cytometry [277]) | |
Neuro-protective roles | Microglia prevent dysfunctional pro-inflammatory astrocyte responses in toxin-mediated demyelination enabling an inflammatory/regenerative switch required for the initiation of remyelination [352] CSFR signalling causes the expansion of a CD11c + microglia population, corresponding with suppression of disease progression and disease severity, and the reduction in demyelination and the loss of oligodendrocytes [347] Stimulation of P2X4R on microglia enhances an acidic shift in lysosomes which increases microglial phagocytic capacity to promote myelin clearance and remyelination [362] Blocking TREM-2 or mice deficient in TREM-2, revealed a failure of microglia to upregulate genes required for lipid metabolism and phagocytosis, and resulted in the exacerbation of EAE [254, 255] Microglia are protective in the development of secondary progressive MS by suppressing T cell activation and reducing neuronal degeneration [309] | NO+ and Arg1+ monocyte-derived cells may represent CD11b+Ly6ChiLy6G−F4/80+CD93+ cells, a subset of myeloid-derived suppressor cells, capable of suppressing CD4+ and CD8+ T cells through the production of NO in culture [367] Adoptively transferred monocytes treated with the MS drug, glatiramer acetate, reversed EAE paralysis by inducing MHC-II-restricted Treg and T helper 2 cells in an antigen-independent manner [341] |
Neuro- toxic roles | Microglia depleted animals had more mature oligodendrocytes, suggesting that microglia play a neurotoxic role in the acute phase of EAE by preventing oligodendrocyte progenitor cell maturation and remyelination [243] Peli deletion (i.e., Peli−/− mice) [206] and ablation of Tak1 in long-lived CX3CR1+ cells [129] (which includes microglia) attenuated EAE pathology. Peli and TAK1 are involved in production of pro-inflammatory chemokines and cytokines. Thus, microglial proinflammatory mediator production is detrimental in the development of EAE Microglial engulfment of presynaptic termini contributes to synapse loss [342] Targeting microglia and MDMs expressing an ‘oxidative stress signature’ with acivicin decreased axonal damage, demyelination and the infiltration of immune cells into the CNS in EAE, whilst reducing microglia activation and enhancing neuronal survival in microglia-mediated demyelination [224], suggesting that a subpopulation of microglia are neurotoxic in EAE | CCR2 [98, 137, 165, 230] or CD49e [4]-dependent Ly6Chi monocyte infiltration into the spinal cord is necessary for EAE induction [4, 98, 137, 165, 230] and exacerbates disease severity [4] MDM initiate myelin destruction at the Nodes of Ranvier [355] CD11c+CCR2+ MoDC may stimulate myelin-reactive T cells, as selective deletion of MHC-II on both peripheral and CNS-resident CD11c + myeloid cells, but not CNS-resident myeloid cells alone, prevented EAE induction, and CCR2+ peripheral myeloid cells preferentially show long-lasting interactions with autoreactive CD2+ T cells [174] |