Microglial CX3CR1 deficiency regulates the selective vulnerability of cone photoreceptors via STAT3/CCL-ACKR1 signaling in the mouse retina

Selective neuronal vulnerability is a common feature of neurodegenerative disorders. However, the molecular mechanisms that drive this selective vulnerability are not fully understood. Here we observed that microglial CX3CR1 interference induced proinflammatory responses in microglia and astrocytes that were correlated with the selective vulnerability of cone photoreceptors in the mouse retina. Via proteomic analysis, we identified STAT3 as a potential downstream target by which CX3CR1 mediates microglial neurotoxicity. Moreover, single-cell RNA Sequencing analysis revealed that CX3CR1-deficient microglia exhibit eight distinct transcriptomic phenotypes. At the mechanistic level, our data revealed that the involvement of Tnf-dominant microglia occurred mainly via microglia‒cone interactions through CCLs and their receptor, atypical Chemokine Receptor 1 (Ackr1), whose expression was upregulated primarily in cones through NF-κB signaling, leading to selective cone loss. In addition, we found that Cxcl1-dominant microglia primarily communicated with astrocytes via the Bmp2-Bmpr1a/Bmpr1b pair, leading to increased STAT3 levels and, consequently, elevated CCL and CXCL production in astrocytes, which in turn contributed to further cone loss through Ackr1. Overall, our data demonstrate that microglial CX3CR1 deficiency induces selective cone cell death via activation of the STAT3/CCL-ACKR1 signaling pathway, and that targeting CX3CR1/STAT3 could represent a therapeutic strategy to reduce microglial neurotoxicity.