Microglia In Central Nervous System Research Articles

New Insights into Microglia as Therapeutic Targets in Alzheimer’s Disease

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disease, accounting for 60–70% of dementia cases globally. Inflammation of the central nervous system (CNS) caused by microglia is a common characteristic of neurodegenerative illnesses such as Parkinson's disease and AD. Research has recently examined the relationship between neurodegenerative diseases and CNS microglia. Microglial cells comprise 10–15% of all CNS cells and are brain-resident myeloid cells mediating critical processes to support the CNS. Microglia have a variety of receptors that operate as molecular sensors, detecting exogenous and endogenous CNS injuries and triggering an immune response. Microglia serve as brain guardians by boosting phagocytic clearance and providing trophic support to enable tissue repair and maintain cerebral homeostasis, in addition to their traditional immune cell activity. At rest, microglia manage CNS homeostasis by phagocytic action, which removes pathogens and cell debris. Microglia cells that have been "resting" convert into active cells that create inflammatory mediators, protecting neurons and protecting against invading pathogens. Neuronal damage and neurodegenerative disorders are caused by excessive inflammation. Different microglial cells reply at different phases of the disease can lead to new therapy options and reduced inflammatory activity. This review focuses on the potential function of microglia, microglia subtypes, and M1/M2 phenotypic changes associated with neurodegenerative disorders. Microglial membrane receptors, the involvement of microglia in neuroinflammation, microglial targets in AD and the double role of microglia in AD pathogenesis are also discussed in this review.

CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice

AbstractChronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow–derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R–treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr–/– grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.

Clonal Derivation and Dynamics in Rhesus Macaques Following Hematopoietic Stem Cell Transplantation and the Impact of Clonal Hematopoiesis

Microglia (MG) are the resident macrophages of the central nervous system (CNS). Under steady-state conditions, MG play essential roles in immune surveillance; phagocytosis and processing of pathogens, dying cells and protein aggregates; and synaptic pruning to maintain neuronal health. MG dysfunction has been linked to various CNS disorders, including neurodegenerative disorders such as Alzheimer's disease, with multiple pathways implicated, including increased and prolonged activation with excessive release of pro-inflammatory mediators. Lineage tracing studies in mice have demonstrated that yolk sac macrophages form the CNS MG compartment during development, with little ongoing replacement from circulating monocyte/macrophages at steady state or even following hematopoietic stem/progenitor cell (HSPC) transplantation. However, improvements in disease outcomes in human patients with CNS disorders such as adrenoleukodystrophy and metachromatic leukodystrophy following HSPC gene therapies have suggested that adult HSPC-derived cells can contribute to MG function. Recently, Bouzid et al reported that individuals with somatic HPSC mutations in hematopoietic expansion driver genes (clonal hematopoiesis/CH) had a significantly lower risk of Alzheimer's disease (AD). The same study utilized nuclear chromatin profiling of a small set of postmortem brain samples to suggest substantial contribution of CH-derived HSPC to the MG compartment. The authors suggested that enhanced function of CH-derived MG enables them to better clear AD plaques. To more directly investigate the replacement and clonal source of adult CNS resident MG/myeloid cells by HSPC-derived cells and to and assess the impact of CH mutations on MG replacement, we utilized clinically-relevant rhesus macaque (RM) models. Fresh MG and other tissue-resident myeloid cells were purified from the brains of RM that had undergone autologous transplantation 2- 9 years previously with HSPCs transduced with a barcoded lentiviral vector expressing GFP following ablative total body irradiation (TBI, n=6) (Koelle et al, Blood, 2017) or busulfan (n=1, vector without GFP)(Abraham et al, MTMCD, 2023); or HSPCs engineered to carry TET2 mutations using CRISPR/Cas9 (n=2)(Shin et al, Blood, 2022). In addition, we studied an aged RM with natural CH ( RUNX1 mutation) in order to investigate MG replacement in the absence of conditioning and transplantation. We optimized RM MG (CD45+CD11b+CX3CR1+) and CNS myeloid cell (CD45+CD11B+CX3CR1-) purification. To ensure separation of bona fide tissue-resident CNS cells away from perivascular cells or contaminating blood, we incorporated CD45-specific antibody serial intravascular staining (SIVS) (Mortlock et al., 2022) and sorted SIVS- parenchymal MG, SIVS- perivascular MG, and SIVS+ myeloid cells. In all 6 TBI-conditioned lentiviral-barcoded animals, at most 2% of tissue-resident SIVS- MG cells were GFP+ (Fig 1A), with a mean ratio of <0.01 compared to the level of GFP+ circulating blood monocytes in each animal (Fig 1B). Barcode analyses demonstrated similar clonal derivation of GFP+ MG cells to peripheral blood (PB) monocytes, representing output from stable long-term multipotent HSPC clones. A higher MG repopulation level was found in the busulfan-conditioned animal by vector copy number. MG replacement with CH-derived cells was no higher absolutely or relative to blood monocytes in the two engineered TET2-CH animals nor in the aged animal with natural CH (Fig 1B). These results demonstrate only low-level replacement of MG from HSPCs even many years following ablative conditioning and autologous transplantation, and no evidence for enhanced repopulation in the setting of engineered or natural clonal hematopoiesis. The clonal ontogeny of the HSPC-derived MG cells matched that of blood myeloid cells. Further characterization of MG derived from transplanted HSPCs versus control MG is ongoing, as is functional characterization of CH versus unmutated macrophages, asking whether mutated cells are hyper-functional. Our clinically-relevant macaque model provides insights into MG ontogeny, and information relevant to improving CNS-directed HSPC gene therapies, as well as information relevant to interpreting a potential protective impact of CH on human AD.

Migraine and major depression: localizing shared genetic susceptibility in different cell types of the nervous systems.

There is a bidirectional relationship between migraine and major depression disorder (MDD). They likely share important risk genes associated with different cell types in the central nervous system (CNS) and peripheral nervous system (PNS). Profiling the expression of these genes in specific cell types is critical in understanding the pathophysiology of the relationship between migraine and MDD. Associated genes shared by migraine and MDD were identified by consolidating multiple curations of human disease-gene associations. Subsequently, the expression of overlapping genes was profiled and compared across the different cell types in CNS, PNS and neurovascular cells using eight single cell RNA sequencing datasets, including two human CNS datasets, two mouse CNS datasets, one human PNS dataset and three mouse PNS datasets. 45 shared genes between migraine and MDD were identified. Consistently found in all eight datasets, dopaminergic and serotonergic neurotransmitters were broadly expressed in CNS and PNS cell types. Glutamatergic and endocannabinoid genes were specifically expressed in CNS neurons and astrocytes. Synthesis and/or Release and Binding of Neuropeptides were specifically expressed in PNS peptidergic nociceptor (PEP). Genes related to inflammatory factors and immune responses were specifically expressed in CNS microglia. Among which, IL1B and COMT were highly expressed in CNS microglia cells. Single cell RNA sequencing of the CNS and PNS helps to identify the shared genes between migraine and MDD that are enriched in specific cell types. The findings provide new insight in understanding the underlying mechanism of action for the bidirectional co-morbidity between migraine and MDD.

N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R)

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair.

In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.

Investigating the protective contribution of PLCG2 P522R variant in microglia‐mediated immune pathways in Alzheimer’s Disease

AbstractBackgroundAs the main innate immune cell in central nervous system (CNS), microglia plays an indispensable roles in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s Disease (AD). Large scale population studies have identified an AD‐associated rare coding variant in the Phospholipase C Gamma 2 (PLCG2) locus (rs72824905, P522R, P=5.38x10‐10, odds ratio = 0.68), which potentially offers protection against AD. This variant is associated with lower Aβ1‐42 and pTau181 levels in patients, as well as delays cognitive decline in mild cognitive impairment (MCI) progression. It has been reported that PLCG2 highly expresses in microglia in CNS and mainly involved in immune response, therefore, PLCG2 P522R variant may be a central player in the microglial‐mediated immune pathways during AD pathogenesis.MethodWe generated a PLCG2522R/R knock‐in mouse model carrying this human variant with CRISPR‐mediated gene editing. To explore the protective nature of PLCG2 P522R variant, we generated PLCG2522R/R; 5XFAD mouse model by crossing PLCG2522R/R knock‐in model with the 5XFAD mice, and accessed major AD phenotypes including Aβ load and microgliosis in vivo.ResultOur data showed that PLCG2522R/R;5XFAD mice exhibited attenuated AD pathologies compared with PLCG2522P/P;5XFAD mice, including less burden of Aβ in cortical and hippocampal regions, and less Aβ‐associated microglia clustering around Aβ plaques at early stage of AD.Conclusion PLCG2 P522R variant can protect against AD pathology in PLCG2522R/R;5XFAD mice, which may likely link to its hypermorphic effect in immune pathways, so that PLCG2522R/R microglia potentially have improved phagocytotic function and restrict Aβ accumulation in brain. We believe that investigating the protective role of PLCG2 P522R mutation may help us better understand the neuroinflammation aspect of AD pathogenesis, and provide new strategies to developing clinical therapy in the future.

Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage.

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH.

Abstract 4 Umbilical Cord-Derived Mesenchymal Stromal Cells Suppress Neuroinflammation and Promote Remyelination in the Spinal Cord

IntroductionMesenchymal stromal cells (MSCs) are one of the most widely tested cell therapies due to their ability to suppress inflammation. Demyelinating diseases of the central nervous system (CNS) are commonly accompanied by neuroinflammation, including infiltrating proinflammatory leukocytes and activation of resident macrophages (microglia and border-associated macrophages in the meninges). The precise mechanism of how MSCs suppress neuroinflammation is unclear; however, we recently described a novel pathway where MSCs physically interact with macrophages to reprogram the immune response through the transfer of a cytoplasmic organelle called a processing body (p-body).ObjectiveWe set out to study how human umbilical cord tissue-derived MSCs interact with CNS microglia and border macrophages to protect in a mouse model of spinal cord demyelination.MethodsWe manufactured several MSC lines under GMP conditions and tested their ability to interact with CNS macrophages and promote remyelination in multiple preclinical assays. To determine if p-bodies are critical for these steps, we depleted p-bodies using CRISPR/Cas9 targeting to DDX6. To test for effects on acute demyelination, we injected lysophosphatidylcholine (LPC) into the spinal cord or added LPC to organotypic cerebellar slice cultures. To test direct effects on microglia activation, we treated primary microglia or a microglia cell line with lipopolysaccharide.ResultsWe determined that MSC promoted remyelination in the spinal cord and that this was dependent on p-bodies. MSC directly contacted CNS macrophages and inhibited their activation. Using primary microglia and a microglia cell line, we determined that MSCs suppress the release of proinflammation cytokines, IL-6, and TNF.DiscussionWe determined that MSCs suppress microglial cell activation and enhance remyelination of the spinal cord. Our study offers insight into a novel mechanism about how MSCs can alter the immune response via transferring p-bodies and enhance remyelination in CNS. Furthermore, our results may lead to a quick and simple potency assay to establish the efficacy of MSCs for suppressing neuroinflammation.

Microglia depletion as a therapeutic strategy: friend or foe in multiple sclerosis models?

Multiple sclerosis is a chronic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation, genetic predisposition, and environmental factors. The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology, playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration. Even though reactive microglia can damage tissue and heighten deleterious effects and neurodegeneration, activated microglia also perform neuroprotective functions such as debris phagocytosis and growth factor secretion. Astrocytes can be activated into pro-inflammatory phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia, which could also mediate neurodegeneration. This A1 phenotype inhibits oligodendrocyte proliferation and differentiation and is toxic to both oligodendrocytes and neurons. However, astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism. A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation, progression, and resolution of the disease. The colony-stimulating factor-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia. Importantly, as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling, colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain. In this context, the present review discusses the impact of microglial depletion through colony-stimulating factor-1 receptor inhibition on demyelination, neurodegeneration, astroglial activation, and behavior in different multiple sclerosis models, highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.

Glycogen synthase kinase-3β inhibition decreases inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.

Bone is the preferential site of metastasis for breast cancer. Invasion of cancer cells induces the destruction of bone tissue and damnification of peripheral nerves and consequently induced central sensitization which contributes to severe pain. Herein, cancer induced bone pain (CIBP) rats exhibited destruction of tibia, mechanical allodynia and spinal inflammation. Inflammatory response mainly mediated by astrocyte and microglia in central nervous system. Our immunofluorescence analysis revealed activation of spinal astrocytes and microglia in CIBP rats. Transmission electron microscopy (TEM) observations of mitochondrial outer membrane disruption and cristae damage in spinal mitochondria of CIBP rats. Proteomics analysis identified abnormal expression of proteins related to mitochondrial organization and function. Intrathecally, injection of GSK‐3β activity inhibitor TDZD‐8 significantly attenuated Drp1‐mediated mitochondrial fission and recovered mitochondrial function. Inhibition of GSK‐3β activity also suppressed NLRP3 inflammasome cascade and consequently decreased mechanical pain sensitivity of CIBP rats. For cell research, TDZD‐8 treatment significantly reversed TNF‐α induced mitochondrial membrane potential (MMP) deficiency and high mitochondrial reactive oxygen species level. Taken together, GSK‐3β inhibition by TDZD‐8 decreases spinal inflammation and relieves cancer induced bone pain via reducing Drp1‐mediated mitochondrial damage.

Biological activity of interferon gamma and lipopolysaccharide on the nitric oxide production in C6 astroglioma cells and some unexpected effects of potentization

Background: A proinflammatory environment is a hallmark of several neurodegenerative diseases where astrocyte involvement is also well established. Astrocytes and microglia in central nervous system are mainly involved in the release of cytokines, oxygen free radicals and nitric oxide (NO). Several studies on C6 astroglioma cells, a widely used in vitro model for these events, demonstrated that co-stimulation of this cell line with bacterial lipopolysaccharide (LPS) and interferon gamma (IFN-) induces a synergistic nitric oxide synthase (iNOS) expression.1 In our laboratory we are using this versatile cell model in order to carefully investigate dose-response effects of various putative agonists or inhibitors and to assess the possible changes provoked in those agents by different procedures of dilution and succussion (agitation) (potentization according to the homeopathic terminology).

Research progress in pathogenesis and treatment of neuroinflammation

Neuroinflammation, defined as an inflammatory response mediated by central nervous system astrocyte, Microglia and endothelial cells, disrupts homeostasis and is typical of many Neurodegeneration. The DA receptor family is mainly expressed in Microglia, and microglia-induced neuroinflammation is an important pathogenesis of Neurodegeneration, this article reviews the pathogenesis and treatment of neuroinflammation.

Sex-Specific Effects of Microglia-Like Cell Engraftment during Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells. In this study, tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice. Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein (MOG) one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages. We demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice. Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells. An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity

Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.

Microinjection of a growth factor cocktail affects activated microglia in the neocortex of adult rats.

Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factors can activate multiple signaling pathways in central nervous system microglia and can regulate their immune effects, but whether growth factors can affect the morphological characteristics and ultrastructure of microglia has not been reported. After microinjecting 300 nL of a growth factor cocktail, including 10 μg/mL epidermal growth factor, 10 μg/mL basic fibroblast growth factor, 10 μg/mL hepatocyte growth factor and 10 μg/mL insulin-like growth factor into adult rat cortex, we found that the number of IBA1-positive microglia around the injection area increased significantly, indicating local activation of microglia. All CD68-positive labeling co-localized with IBA1 in microglia. Cell bodies and protrusions of CD68-positive cells were strongly attached to or were engulfing neurons. Characteristic huge phagosomes were observed in activated phagocytes by electron microscopy. The phagosomes generally included non-degraded neuronal protrusions and mitochondria, yet they contained no myelin membrane or remnants, which might indicate selective phagocytosis by the phagocytes. The remnant myelin sheath after phagocytosis still had regenerative ability and formed "myelin-like" structures around phagocytes. These results show that microinjection of a growth factor cocktail into the cerebral cortex of rodents can locally activate microglia and induce selective phagocytosis of neural structures by phagocytes. The study was approved by the Institute of Laboratory Animal Science, Beijing Institute of Basic Medical Sciences (approval No. IACUC-AMMS-2014-501) on June 30, 2014.

Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE)

Toll-like receptor 4 (TLR4) play a key role in activating the innate immune system during pathogen recognition. In the pathogenesis of multiple sclerosis (MS), activated TLR4 together with myeloid differentiation primary response gene 88 (MyD88) produce an inflammatory microenvironment that promotes the differentiation of microglia into the M1 phenotype, who plays a key role in the pathogenesis of MS. Interleukin-1 receptor-associated kinase (IRAK)-M is specifically expressed in microglia in central nervous system (CNS) and act as a negative regulator of TLR4-MyD88 signaling pathway. Moreover, previous studies have shown that IRAK-M promotes the differentiation of type 2 microglia; however, its role in MS has not been explored. In the present study, we demonstrated that IRAK-M expression is elevated during EAE, and IRAK-M−/− mice significantly accelerated course and increased severity of disease, accompanied by a visible increase of the M1 microglia infiltrated. In conclusion, these data indicates that IRAK-M significantly improves EAE onset through down-regulation of the TLR4-MyD88 signaling pathway, which finally leads to differentiation of M2 phenotype in the microglia. Our study suggests that IRAK-M may be a potential therapeutic target for the treatment of MS.

Microglia emerge as central players in brain disease.

There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

HDAC3 controls homeostasis of retina-resident microglia derived from embryonic precursors

Abstract Microglia are tissue resident macrophages of the central nervous system (CNS) that function in CNS maintenance and innate immune defense. Macrophages are mediators of immune threshold and thus implicated in disease pathogenesis. Compared to research efforts on CNS microglia, relatively little is known about microglial development or homeostasis in the retina. Histone deacetylases (HDACs) are enzymes known to regulate gene expression by modifying chromatin structure. Here, we use a murine model with conditional deletion of HDAC3 induced by Colony Stimulating Factor 1 Receptor (Csf1r) Cre to determine the consequence of HDAC3 depletion on microglial development and homeostasis in the retina. Macrophages were identified using CD11b and F4/80 markers. Retinal microglial populations were assessed in mice at embryonic day 14.5 (E14.5) as well as at birth and 4-weeks old. A population of CD11b+F4/80bright retinal microglia were identified as early as E14.5, indicating that retinal microglia are derived from seeding of embryonic progenitors from the yolk sac or fetal liver. Although the frequency of retinal microglia was comparable at embryonic stage and at birth, it was significantly reduced (P = 0.008) in HDAC3 KO mice at 4 weeks old. Moreover, retinal microglia were partially radio-resistant, and could be repopulated by fetal liver cells transferred from WT but not HDAC3 KO embryos. This is the first report to show that retina-resident microglia are derived from embryonic precursors and that HDAC3 controls microglial homeostasis in adult retina. HDAC3 may serve as a promising therapeutic target for microglial immune-reactive pathologies such as age-related macular degeneration.

Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice.

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35–55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35–55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35–55.