Dataset Information

Dual extra-retinal origins of microglia in the model of retinal microglia repopulation.

ABSTRACT: Elucidating the origin of microglia is crucial for understanding their functions and homeostasis. Previous study has indicated that Nestin-positive progenitor cells differentiate into microglia and replenish the brain after depleting most brain microglia. Microglia have also shown the capacity to repopulate the retina after eliminating all retinal microglia. However, the origin(s) of repopulated retinal microglia is/are unknown. In this study, we aim to investigate the origins of repopulated microglia in the retina. Interestingly, we find that repopulated retinal microglia are not derived from Nestin-positive progenitor cells. Instead, they have two origins: the center-emerging microglia are derived from residual microglia in the optic nerve and the periphery-emerging microglia are derived from macrophages in the ciliary body/iris. Therefore, we have for the first time identified the extra-retinal origins of microglia in the adult mammalian retina by using a model of microglial repopulation, which may shed light on the target exploration of therapeutic interventions for retinal degenerative disorders.

SUBMITTER: Huang Y

PROVIDER: S-EPMC5827656 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dual extra-retinal origins of microglia in the model of retinal microglia repopulation.

Huang Yubin Y Xu Zhen Z Xiong Shanshan S Qin Guangrong G Sun Fangfang F Yang Jian J Yuan Ti-Fei TF Zhao Lei L Wang Ke K Liang Yu-Xiang YX Fu Lin L Wu Tianzhun T So Kwok-Fai KF Rao Yanxia Y Peng Bo B

Cell discovery 20180227

Elucidating the origin of microglia is crucial for understanding their functions and homeostasis. Previous study has indicated that Nestin-positive progenitor cells differentiate into microglia and replenish the brain after depleting most brain microglia. Microglia have also shown the capacity to repopulate the retina after eliminating all retinal microglia. However, the origin(s) of repopulated retinal microglia is/are unknown. In this study, we aim to investigate the origins of repopulated mic ...[more]

PMID: 29507754

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Project description:Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is a leading complication of diabetes mellitus. Medical interventions slow the progression of disease. However, current therapies do not specifically target microglia, a cell type implicated in mediating disease development. Microglia-mediated inflammation in the diabetic retina is regulated via CX3CR1-FKN signaling, where FKN serves as a dampening signal for microglial activation. Studying this signaling axis is important as polymorphic variants of CX3CR1 are found in 25% of the human population, hCX3CR1I249/M280, resulting in a receptor with lower binding affinity for FKN. Furthermore, disrupted CX3CR1-FKN signaling in CX3CR1-KO and FKN-KO mice leads to exacerbated microglial activation, robust neuronal cell loss and substantial vascular damage in the diabetic retina. Thus, studies to characterize the effects of hCX3CR1I249/M280-expression in microglia-mediated inflammation in the diseased retina are potentially clinically relevant to identify microglia-specific therapies. Our results show that hCX3CR1I249/M280 mice are significantly more susceptible to microgliosis and production of Cxcl10 and TNFα under acute inflammatory conditions. This pathology is exacerbated under diabetic conditions and coincides with robust neuronal loss in comparison to CX3CR1-WT mice. Therefore, to further investigate the role of hCX3CR1I249/M280-expression in microglial responses, we pharmacologically depleted microglia using PLX-5622, a CSF-1R antagonist. PLX-5622 treatment led to a robust (~70%) reduction in Iba1+ microglia in all non-diabetic and diabetic mice. CSF-1R antagonism in diabetic CX3CR1-WT prevented TUJ1+ axonal loss, angiogenesis and fibrinogen deposition. In contrast, PLX-5622 microglia depletion in CX3CR1-KO and hCX3CR1I249/M280 mice did not alleviate TUJ1+ axonal loss or angiogenesis. Interestingly, PLX-5622 treatment reduced fibrinogen deposition in CX3CR1-KO mice but not in hCX3CR1I249/M280 mice, revealing that hCX3CR1I249/M280 receptor variant mice behave differently in terms of vascular pathology compared to CX3CR1-KOs. mRNAseq gene expression analysis in CX3CR1-WT retinal isolates revealed that PLX-5622-induced microglia depletion and repopulation induced a downregulation in genes associated with microglial activation and phagocytosis, B2m, Cx3cr1, and Trem2, and complement-associated synaptic pruning, C1qa, C1qb, and C1qc. Furthermore, mRNAseq analysis of PLX-5622 treated CX3CR1-WT retinas showed lower fold changes in genes encoding proinflammatory mediators (Cxcl10, Ccl2, Il6, Cxcl1, Selp, Il12b, Tnf, Cxcl2, Icam1 and Vcam1) in comparison to diabetic + normal chow mice.

Dataset Information

Dual extra-retinal origins of microglia in the model of retinal microglia repopulation.

Publications

Dual extra-retinal origins of microglia in the model of retinal microglia repopulation.

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