Toll-Like Receptor 4 as a Key Regulator of Retinal Progenitor Cell Proliferation

Abstract

Purpose: : To test the involvement of Toll-like receptor 4 (TLR4) in the retinal neurogenic process.

Methods: : Retinas from postnatal day 6 were analyzed by RT-PCR and immunohistochemistry for TLR4 expression. The proliferation and neuronal differentiation of retinal progenitor cells (RPCs) was compared in wild-type and TLR4 deficient mice that received intraperitoneal injections of the cell proliferation marker BrdU. RPCs were cultured in vitro and tested for TLR4 expression and for proliferation and differentiation in the present and absent of TLR4 ligand. Growth factor administration was preformed in wild-type and TLR4 deficient mice in order to test the effect of TLR4 under permissive proliferation conditions.

Results: : TLR4-deficient mice showed an enhanced proliferation of cells reminiscent of RPCs during the early postnatal period. In vitro experiments demonstrated that TLR4 could act as an intrinsic regulator of RPC fate decision. While increased TLR4 expression in the eye correlated with the postnatal cessation of cell proliferation, deficiency in TLR4 was not sufficient to extend the proliferation phase. Yet, expansion of this proliferation period by supplementation of proliferation-promoting growth factors was much more pronounced in TLR4 deficient mice than in their wild-type controls, indicating on the restrictive role of TLR4 under permissive proliferation conditions.

Conclusions: : In this study, we show that in the mammalian eye, the function of the immuno-receptor TLR4 extends beyond regulation of the innate immune response, as it restricts RPC proliferation.

Keywords: immunomodulation/immunoregulation • retina • proliferation