Department of Ophthalmology, University of Florida, Gainesville, FL, 32610, USA.
Sci Rep. 2018 Jun 14;8(1):9115. doi: 10.1038/s41598-018-27479-x.
Retinal degeneration is a common cause of irreversible blindness and is caused by the death of retinal light-sensitive neurons called photoreceptors. At the onset of degeneration, stressed photoreceptors cause retinal glial cells to secrete neuroprotective factors that slow the pace of degeneration. Leukemia inhibitory factor (LIF) is one such factor that is required for endogenous neuroprotection. Photoreceptors are known to release signals of cellular stress, called damage-associated molecular patterns (DAMPs) early in degeneration, and we hypothesized that receptors for DAMPs or pattern recognition receptors (PRRs) play a key role in the induction of LIF and neuroprotective stress responses in retinal glial cells. Toll-like receptor 2 (TLR2) is a well-established DAMP receptor. In our experiments, activation of TLR2 protected both male and female mice from light damage, while the loss of TLR2 in female mice did not impact photoreceptor survival. In contrast, induction of protective stress responses, microglial phenotype and photoreceptor survival were strongly impacted in male TLR2 mice. Lastly, using publicly available gene expression data, we show that TLR2 is expressed highly in resting microglia prior to injury, but is also induced in Müller cells in inherited retinal degeneration.
视网膜变性是一种常见的不可逆失明原因，是由称为光感受器的视网膜光敏感神经元死亡引起的。在变性开始时，应激光感受器会导致视网膜神经胶质细胞分泌神经保护因子，从而减缓变性的速度。白血病抑制因子 (LIF) 就是这样一种内源性神经保护所必需的因子。已知光感受器在变性早期会释放称为损伤相关分子模式 (DAMP) 的细胞应激信号，我们假设 DAMPs 的受体或模式识别受体 (PRR) 在诱导 LIF 和视网膜神经胶质细胞的神经保护应激反应中起关键作用。Toll 样受体 2 (TLR2) 是一种成熟的 DAMPs 受体。在我们的实验中，TLR2 的激活可保护雄性和雌性小鼠免受光损伤，而雌性小鼠 TLR2 的缺失则不会影响光感受器的存活。相比之下，在雄性 TLR2 小鼠中，诱导保护性应激反应、小胶质细胞表型和光感受器存活受到强烈影响。最后，使用公开的基因表达数据，我们表明 TLR2 在损伤前的静息小胶质细胞中高表达，但在遗传性视网膜变性的 Müller 细胞中也被诱导。
