Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa.

Alonso Sánchez-Cruz,Pedro De La Villa,Enrique J De La Rosa,Catalina Hernández-Sánchez,Andrea C Méndez,Ignacio Lizasoain

doi:10.3390/ijms22157815

Abstract

Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6brd10/rd10 (rd10) and RhoP23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP.

Highlights

Retinitis pigmentosa (RP) is a group of retinal genetic dystrophies responsible for the most prevalent forms of hereditary blindness
We show that the expression of Tlr2 and its adaptor molecules is increased in both rd10 and P23H/+ retinas with respect to age-matched wild type (WT) retinas
In addition to carrying two distinct, unrelated causative mutations, the two models differ considerably in terms of the temporal progression of the disease; in the rd10 mouse most rods are lost within 4 weeks of birth, while in the P23H/+ mouse rod loss occurs over several months

Summary

Introduction

Retinitis pigmentosa (RP) is a group of retinal genetic dystrophies responsible for the most prevalent forms of hereditary blindness. RP encompasses a range of genetically heterogeneous disorders caused by more than 3000 different mutations in over 60 genes (https://sph.uth.edu/retnet/sum-dis.htm (accessed on 6 June 2021)). There is no effective treatment to date, and gene therapy is a promising therapeutic strategy, its applicability is limited by the genetic diversity of RP and the low prevalence of individual RP-causing mutations. Traits common to all forms of RP include primary dysfunction and death of photoreceptors, which in turn triggers a rapid response in the microglial and macroglial cells of the retina, aimed at restoring tissue homeostasis. The targeting of common alterations could constitute a feasible strategy for treating the wide variety of RP types, regardless of the causative mutation [5,6]

Methods

Results

Conclusion