Tlr4 gene deletion accelerates retinal degeneration in rd10 and P23H/+ murine models of retinitis pigmentosa

Abstract

AbstractPurpose: The photoreceptor degeneration associated to retinitis pigmentosa (RP) is caused by a wide variety of genetic mutations, which greatly complicates the development of a universal effective treatment. As a process independent of the causative mutation, the inflammatory response resulting from neuronal death could represent a potential candidate for a general treatment for RP. In this context, we studied the role of TLR4, one of the main mediators of innate immunity, on the retinal degenerative process in two murine models of RP.Methods: rd10 and P23H/+ mice were used to evaluate the consequences of Tlr4 haploinsufficiency and complete deletion on retinal degeneration. Visual function was evaluated by electroretinographic recordings and optomotor test and retinal cytoarchitecture by immunohistology. The myeloid cell population (main mediators of the innate immune response) reactivity was studied by immunohistology and flow cytometry. Gene expression was assessed by RT‐quantitative PCR.Results: We found that Tlr4 expression was significantly increased in the retina of both RP models. To assess the effect of Tlr4 deletion in PR progression first we confirmed that abrogation of Tlr4 expression did not impair visual function in wild‐type animals. However, Tlr4 deficiency accelerated RP progression in both rd10 and P23H/+ mice. Deletion of a single Tlr4 allele reduced the retinal electroretinographic response and photoreceptor survival in both RP models. Moreover, complete abrogation of Tlr4 further exacerbates this phenotype. These results were confirmed by assessing visual acuity by optomotor test in P23H/+ mice. Microglia analysis showed higher proportion of phagocytic microglia and lower of homeostatic microglia in the photoreceptor layers upon Tlr4 total deletion.Conclusions: The TLR4 receptor exerts a neuroprotective effect on the retinal neurodegenerative process in RP, thus suggesting a potential therapeutic target for the disease.