State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510000, China.
Cell. 2024 Mar 14;187(6):1387-1401.e13. doi: 10.1016/j.cell.2024.01.040. Epub 2024 Feb 26.
The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
Crb1 基因的 Crumbs 同源物 1（CRB1）与视网膜变性有关，最常见的是莱伯先天性黑蒙（LCA）和色素性视网膜炎（RP）。在这里，我们证明了携带 Crb1 的 Rd8 突变的小鼠视网膜存在病灶内细菌。虽然正常的 CRB1 表达在视网膜色素上皮和结肠肠上皮细胞的顶端连接复合物中富集，但 Crb1 突变在这两个部位都抑制了其表达。Rd8 小鼠中，由于外血视网膜屏障和结肠肠上皮屏障的破坏，导致从下消化道（GI）迁移的肠道细菌转移到视网膜，从而导致继发性视网膜变性。全身性细菌耗竭或结肠中正常 Crb1 表达的再引入挽救了与 Rd8 突变相关的视网膜变性，而没有逆转视网膜屏障破裂。我们的数据阐明了 Crb1 突变相关视网膜变性的发病机制，并表明抗菌药物有可能治疗这种毁灭性的致盲疾病。
