Abstract
During the pathogenesis of retinitis pigmentosa (RP), the roles of retinal microglial cells after activation have not been fully elucidated. Herein, experimental RP was induced in Sprague Dawley rats by intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg, and the effects of MNU on the retinas were evaluated, respectively, by retinal histology and electroretinography recordings at serial time points. Time-dependent and gradual loss of photoreceptor cells, disrupted arrangement of the outer nuclear layer (ONL), and significant reductions in both a-wave and b-wave amplitudes were observed. Morphology changes were observed in retinal microglial cells; meanwhile, with time, the number of Iba1-positive microglia and their infiltration into the ONL gradually increased. Furthermore, physical interaction of microglial-Müller cell processes following microglial activation was observed after MNU injection. In addition, Müller cells increased CX3CL1 secretion, enhanced microglial cell migration, and upregulated the CX3CR1 expression of the latter. Our observations implied that, during the pathogenesis of RP by MNU, microglial cells exhibit a prominent morphology change and Müller cells can induce activated microglia infiltration by increasing secretion of the chemotaxis factor, CX3CL1, and promoting the migration of retinal microglial cells. This novel finding highlights a potential therapeutic target aimed at regulating the microglial response.
Highlights
As a heterogeneous retinal disorder, retinitis pigmentosa (RP) is one of the most common causes of severe visual impairment in humans, and the prevalence is approximately 1 in 4000, with approximately 2 million persons affected worldwide (Heckenlively et al, 1988; Hartong et al, 2006)
Our observations demonstrated that retinal microglia exhibited a prominent morphological change and migration into the outer nuclear layer (ONL) during the pathogenesis of RP
Considering the origin similarities between brain microglia and retinal microglia, which are derived from myeloid progenitors (Polazzi and Monti, 2010), we investigated the migration ability of primary microglia isolated from the C57BL/6 mouse brain with supernatant from retinal Müller cells after 48 h in culture
Summary
As a heterogeneous retinal disorder, retinitis pigmentosa (RP) is one of the most common causes of severe visual impairment in humans, and the prevalence is approximately 1 in 4000, with approximately 2 million persons affected worldwide (Heckenlively et al, 1988; Hartong et al, 2006). It is known that causative gene mutations, cell stress, the inflammatory response, and retinal remodeling are involved in the pathogenesis of RP, but the outcome is photoreceptor cell death, which results in peripheral vision loss and night blindness (Illing et al, 2002). Müller Cell Regulated Retinal Microglia cell death. In the central nervous system (CNS), including the retina, microglia are the primary resident immune cell population and the prominent participant in retinal responses to disease, inflammation, and injury (Moalem and Tracey, 2006). A deeper understanding of these issues is likely central to the clarification of the functional importance of inflammatory damage to the retina, and may reveal the mechanisms related to cell death in photoreceptor cells
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