{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T01:54:58Z","timestamp":1786499698771,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY029913, GM060655"],"award-info":[{"award-number":["R01EY029913, GM060655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is a leading complication of diabetes mellitus. There is no cure for DR, and medical interventions marginally slow the progression of disease. Microglia-mediated inflammation in the diabetic retina is regulated <jats:italic>via<\/jats:italic> CX3CR1-FKN signaling, where FKN serves as a calming signal for microglial activation in several neuroinflammatory models. Polymorphic variants of <jats:italic>CX3CR1<\/jats:italic>, <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic>, found in 25% of the human population, result in a receptor with lower binding affinity for FKN. Furthermore, disrupted CX3CR1-FKN signaling in <jats:italic>CX3CR1<\/jats:italic>-KO and <jats:italic>FKN<\/jats:italic>-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 <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic>-expression in microglia-mediated inflammation in the diseased retina are relevant to identify mechanisms by which microglia contribute to disease progression. Our results show that <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> mice are significantly more susceptible to microgliosis and production of <jats:italic>Cxcl10<\/jats:italic> and <jats:italic>TNF\u03b1<\/jats:italic> under acute inflammatory conditions. Inflammation is exacerbated under diabetic conditions and coincides with robust neuronal loss in comparison to <jats:italic>CX3CR1<\/jats:italic>-WT mice. Therefore, to further investigate the role of <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic>-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<jats:sup>+<\/jats:sup> microglia in all non-diabetic and diabetic mice. CSF-1R antagonism in diabetic <jats:italic>CX3CR1<\/jats:italic>-WT prevented TUJ1<jats:sup>+<\/jats:sup> axonal loss, angiogenesis and fibrinogen deposition. In contrast, PLX-5622 microglia depletion in <jats:italic>CX3CR1<\/jats:italic>-KO and <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> mice did not alleviate TUJ1<jats:sup>+<\/jats:sup> axonal loss or angiogenesis. Interestingly, PLX-5622 treatment reduced fibrinogen deposition in <jats:italic>CX3CR1<\/jats:italic>-KO mice but not in <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> mice, suggesting that <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> expressing microglia influences vascular pathology differently compared to <jats:italic>CX3CR1<\/jats:italic>-KO microglia. Currently <jats:italic>CX3CR1<\/jats:italic>-KO mice are the most commonly used strain to investigate CX3CR1-FKN signaling effects on microglia-mediated inflammation and the results in this study indicate that <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> receptor variants may serve as a complementary model to study dysregulated CX3CR1-FKN signaling. In summary, the protective effects of microglia depletion is <jats:italic>CX3CR1<\/jats:italic>-dependent as microglia depletion in <jats:italic>CX3CR1<\/jats:italic>-KO and <jats:italic>hCX3CR1<jats:sup>I249\/M280<\/jats:sup><\/jats:italic> mice did not alleviate retinal degeneration nor microglial morphological activation as observed in <jats:italic>CX3CR1<\/jats:italic>-WT mice.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1130735","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T12:58:40Z","timestamp":1679576320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249\/M280-expressing retina"],"prefix":"10.3389","volume":"14","author":[{"given":"Kaira 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