Inhibition of JNK ameliorates rod photoreceptor degeneration in a mouse model of retinitis pigmentosa

• Published in: FEBS letters 2024-11, Vol.598 (21), p.2683-2701
• Main Authors: Liao, Chunyan, Chen, Shuai, Chen, Xuxu, Yi, Wanying, Fan, Yingying, Chen, Yuewen, Ye, Tao, Chen, Yu
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; inflammation; JNK; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; microglia; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; photoreceptor degeneration; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Retinitis Pigmentosa - drug therapy; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism; Retinitis Pigmentosa - pathology
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14978

Retinitis pigmentosa (RP) is an inherited eye disease that causes progressive vision loss. Microglial activation and inflammation play essential roles in photoreceptor degeneration in RP, although the underlying mechanisms remain unclear. Here, we examined the progressive degeneration of photoreceptors in rd1 mice, a mouse model of RP. We investigated the molecular changes in various retinal cells in rd1 mice using single‐cell RNA sequencing and found that potentiation of JNK signaling is associated with photoreceptor degeneration in RP. Moreover, inflammation‐related molecules, which function downstream of JNK, are elevated in RP. Furthermore, inhibiting JNK alleviates microglial activation and rescues photoreceptor degeneration in rd1 mice. Thus, our findings suggest that targeting JNK is a promising approach for slowing RP progression. In rd1 mice, a mouse model of retinitis pigmentosa, JNK activation is associated with photoreceptor degeneration. Glial cell activation and inflammation‐related molecules, which function downstream of JNK, may lead to photoreceptor degeneration. Meanwhile, JNK‐IN‐8, a specific inhibitor of JNK, rescues rod photoreceptor degeneration by decreasing microglial activation in retinitis pigmentosa.