<i>Cx3cr1-</i>deficient microglia exhibit a premature aging transcriptome

Gyoneva, Stefka; Hosur, Raghavendra; Gosselin, David; Zhang, Baohong; Ouyang, Zhengyu; Cotleur, Anne C.; Peterson, Michael A.; Allaire, Norm; Challa, Ravi; Cullen, Patrick; Roberts, Chris; Miao, Kelly; Reynolds, Taylor L.; Glass, Christopher K.; Burkly, Linda C.; Ransohoff, Richard M.

doi:10.26508/lsa.201900453

Cited by 68 publications

(61 citation statements)

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“…We subsequently analyzed gene expression levels of a panel of microglial markers in MDD cases (n = 68 samples derived from 25 donors) and controls (n = 66 samples derived from 19 donors). We defined three categories: (1) genes with important homeostatic properties (TMEM119 and CX3CR1) [44][45][46], (2) genes upregulated upon immune activation (IL1B and IL6), and (3) genes upregulated in responses to 'anti-inflammatory' triggers (CD163 and MRC1) [47,48]. A PCA of expression levels of those 6 selected genes showed that microglial samples segregated between MDD patients and controls ( Fig.…”

Section: Gene Expression Levels In Microglia From Mdd Patients and Comentioning

confidence: 99%

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

et al. 2020

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Findings from epidemiological studies, biomarker measurements and animal experiments suggest a role for aberrant immune processes in the pathogenesis of major depressive disorder (MDD). Microglia, the resident immune cells of the brain, are likely to play a key role in these processes. Previous post-mortem studies reported conflicting findings regarding microglial activation and an in-depth profiling of those cells in MDD is lacking. The aim of this study was therefore to characterize the phenotype and function of microglia in MDD. We isolated microglia from post-mortem brain tissue of patients with MDD (n = 13-19) and control donors (n = 12-25). Using flow cytometry and quantitative Polymerase Chain Reaction (qPCR), we measured protein and mRNA levels of a panel of microglial markers across four different brain regions (medial frontal gyrus, superior temporal gyrus, thalamus, and subventricular zone). In MDD cases, we found a significant upregulation of CX3CR1 and TMEM119 mRNA expression and a downregulation of CD163 mRNA expression and CD14 protein expression across the four brain regions. Expression levels of microglial activation markers, such as HLA-DRA, IL6, and IL1β, as well as the inflammatory responses to lipopolysaccharide and dexamethasone were unchanged. Our findings suggest that microglia enhance homeostatic functions in MDD but are not immune activated.

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Section: Gene Expression Levels In Microglia From Mdd Patients and Comentioning

confidence: 99%

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

et al. 2020

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“…Previously, we have shown that the LysMCre-Socs3 / mice had higher levels of pSTAT3 in the retina (54). Furthermore, a recent study has shown that CX3CR1-de cient microglia exhibit a premature aging transcriptome (55). It is possible that microglia from the DKO mice may also undergo premature aging although this warrants further investigation.…”

Section: Discussionmentioning

confidence: 93%

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

Peñalva

Little

et al. 2020

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BackgroundWe generated a mouse model of primary microglial dysfunction by deleting two negative immune regulatory genes, Cx3cr1 and Socs3 (in LysM+ cells). This study aimed to understand how primary microglial dysfunction impacts retinal neurons during aging.MethodsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout (DKO), LysMCre-Socs3fl/fl, Cx3cr1gfp/gfp and Socs3fl/fl mice were maintained up to 12 months. Eyes were collected and processed for immunohistochemistry of IBA-1, cone arrestin, secretagogin, PKCα and GABA. Brain microglia from DKO and WT mice were stimulated with LPS + IFNγ or IL4. The expression of TNFα, IL1β, IL6, iNOS, IL12p40, IL23p19, CCL2, CCL5, CXCL2, IL10, CD206 and Arg1 were examined by real-time RT-PCR and protein production was measured by Luminex assay. Retinal explants from C57BL/6J mice were co-cultured with microglia from DKO or WT mice for 24 h, after which the number of cone arrestin+ cells in retinal flatmount were quantified.ResultsIn 3–5 month old mice, the number of microglia in retinal ganglion cell layer (GCL) and inner plexiform layer (IPL) were comparable in all strains. The DKO mice had a significantly higher number of microglia in the outer plexiform layer (OPL) but significantly lower numbers of cone arrestin+, secretagogin+ and GABA+ cells compared to Socs3fl/fl and single KO mice. During aging, 57% of the DKO mice died before 12 months old. The 10–12 months old DKO mice had significantly highers number of microglia in GCL/IPL and OPL than age-matched Socs3fl/fl and single KO mice. The aged DKO mice developed retinal pigment epithelial (RPE) dysmorphology accompanied by subretinal microglial accumulation. The number of photoreceptors, bipolar cells (Secretagogin+ or PKCα+) and GABA+ amacrine cells was significantly lower in aged DKO mice compared to age-matched Socs3fl/fl and single KO mice. Microglia from DKO mice showed significantly higher levels of phagocytic activity and produced higher levels of TNFα, IL6, CCL2, CCL5, CXCL2 and CXCL10 compared to microglia from Socs3fl/fl mice. Co-culture of retinal explants with DKO microglia (pre-treated with LPS + IFNγ or IL4) significantly reduced cone photoreceptor survival.ConclusionsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp DKO mice displayed primary microglial dysfunction and developed age-related retinal microgliopathy characterized by aggragated microglial activation and multiple retinal neuronal and RPE degeneration.Trial registration: Not applicable. The article does not contain any results from human participants.

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“…In this regard, two recent studies support these results. The first one determined that Cx3cr1 −/− microglia present a lower phagocytic and migratory capacity per se [ 242 ], while the second revealed that Cx3cr1 −/− microglia of young animals are very similar to the wild type (WT) microglia of older animals [ 243 ]. On the basis of their findings, the authors of the latter study suggested that the absence of CX3CR1 confers a premature aging transcriptome to these cells, accompanied by a decrease in phagocytosis.…”

Section: Neuron–microglia Crosstalk: Implications Of the Cx3cl1–cxmentioning

confidence: 99%

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

2020

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Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

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Cx3cr1-deficient microglia exhibit a premature aging transcriptome

Abstract: Gyoneva et al use RNA-seq to show that Cx3cr1-deficient microglia in young mice display a gene expression profile similar to microglia in aged mice, suggesting premature microglial aging.

Cited by 68 publications

References 65 publications

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

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