Blue Light Induced CL-11/C3/CR1 Signaling Activates but Cannot Rescue Microglial Efferocytosis in RPE Injury
Excessive blue light exposure has been implicated in retinal degeneration. However, the mechanisms by which photodamaged retinal pigment epithelial (RPE) cells mediate microglial dysfunction remain unclear. Blue light exposure caused retinal thinning in vivo and RPE cell death both in vivo and in vitro. HMC3 microglia cultured in conditioned media from photodamaged ARPE-19 cells exhibited impaired efferocytosis, as evidenced by a reduced phagocytic index and the downregulation of the key phagocytic receptors TYRO3 and MERTK. Transcriptomic profiling of HMC3 microglia cultured with conditioned media from control or photodamaged ARPE-19 cells revealed enrichment of complement-related pathways, with CR1, CR2, and C3 markedly upregulated after photodamage. Furthermore, CR1 knockdown further impaired microglial phagocytic capacity and downregulated efferocytic markers, including CD16, TREM2, MERTK, TYRO3, and SCARB1. Mechanistically, blue light induced robust CL-11 upregulation in ARPE-19 cells, increased downstream C3b generation, and elevated CR1 expression in HMC3 cells. Although photodamage upregulated CL-11, which activated the C3b CR1 axis and partially promoted microglial efferocytosis, this compensatory response failed to restore microglial efferocytosis under phototoxic stress.