Understanding the mechanism of retinal detachment-induced photoreceptor apoptosis: neuroprotective treatments for photoreceptor apoptosis

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In retinal detachment and in several other visual disorders, photoreceptor apoptosis represents the major cause of vision loss. The mechanisms underlying photoreceptor apoptosis, however, remain elusive. Here, we review our recent publications on the pathogenesis of retinal detachment-induced photoreceptor apoptosis and discuss the critical role of monocyte chemoattractant protein-1 (MCP-1) in mediating photoreceptor apoptosis in an experimental rodent model of retinal detachment. Elevated levels of MCP-1 are found in vitreous samples from patients with retinal detachment. MCP-1 expression is similarly increased in our rodent model after retinal detachment, with MCP-1 expression being detected in Muller glia. Moreover, CD11b-immunopositive macrophages/microglia are recruited into the detached retina. Interestingly, the suppression of MCP-1 with an MCP-1—blocking antibody or through MCP-1 gene deletion, as in MCP-1—deficient mice, significantly reduces macrophage/microglia infiltration and photoreceptor apoptosis. To investigate whether MCP-1 contributes to photoreceptor apoptosis by directly affecting photoreceptors or by indirectly affecting photoreceptors through recruited macrophages/microglia, we examined the effect of MCP-1 on primary retinal mixed cultures and the induction of retinal detachment in Mac-1 (CD11b/CD18)-deficient mice. Our data showed that MCP-1 cytotoxicity toward cultured photoreceptors occurs through resident microglia. Moreover, eliminating macrophage/microglia infiltration in vivo decreases photoreceptor apoptosis after retinal detachment. Thus, retinal detachment induces increased expression of MCP-1 in Müller cells and increased infiltration and activation of macrophages/microglia, resulting in photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in retinal detachment and other central nervous system diseases that share a common etiology.