INFLAMMATION OF THE RETINAL PIGMENT EPITHELIUM DRIVES EARLY-ONSET PHOTORECEPTOR DEGENERATION IN MERTK-ASSOCIATED RETINITIS PIGMENTOSA

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation is determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation, even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk -/- mice. Neither inflammation nor severe, early-onset PR degeneration were observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function. (C57BL/6, Tyro3-/-V1 and Mertk-/-V2Tyro3-/-V2 ) and (WT129 and Itgb5-/-) RPE were collected at post-natal day 25 (1 hour after light onset) and processed for RNA sequencing与MERTK突变相关的早发性严重光感受器（photoreceptor, PR）退行性病变，既往认为是由视网膜色素上皮（retinal pigment epithelium, RPE）的吞噬功能障碍所导致。然而，Mertk敲除小鼠模型中PR退行性病变的严重程度与发病时机，由Mertk的旁系同源基因Tyro3的功能减退型表达或缺失所决定。本研究发现，Mertk缺失联合Tyro3表达下调/缺失，可在小鼠睁眼之前即引发RPE炎症反应；初期的RPE炎症会发生级联扩散，进而累及小胶质细胞活化、PR退行性病变并伴随单核细胞浸润。使用JAK1/2抑制剂芦可替尼（ruxolitinib）抑制RPE炎症，可减轻Mertk敲除（Mertk-/-）小鼠的PR退行性病变程度。仅存在吞噬功能缺陷的小鼠，既未出现炎症反应，也未发生早发性严重PR退行性病变。综上，炎症反应驱动了与Mertk功能缺失相关的早发性严重PR退行性病变。本研究收集了出生后第25天（光照开始后1小时）的(C57BL/6、Tyro3-/-V1及Mertk-/-V2Tyro3-/-V2)以及(WT129与Itgb5-/-)小鼠的RPE组织，并对其进行RNA测序（RNA sequencing）分析。