Interleukin-17-Mediated Protective Cytokine Signaling Against Degeneration of the Retinal Pigment Epithelium
Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal gd T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to delve deeper into the mechanisms involved. We found that gd T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6 (IL-6). This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal gd T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia. Overall design: CD45+ cells from mouse choroid were sorted by flow cytometry and analyzed by scRNA-seq