The role of TAK1 in microglia during retinal degeneration in rd10 mouse model of human retinitis pigmentosa

Abstract

Retinitis Pigmentosa (RP) is a group of inherited retinal degeneration diseases, which can cause gradual death of photoreceptors. The typical characteristics of RP are narrowed visual field and night blindness which have a greatly impact on RP patients' life quality. Nowadays, treatment for RP is few and with limited effectiveness. The mechanisms for photoreceptor death in RP are not fully elucidated. In recent studies, neuroinflammation has been suggested to contribute to the pathogenesis of RP but the underlying molecular mechanisms are still unclear. In previous research, TAK1's blockage mitigated the increase of proinflammatory factors in several inflammatory diseases. In this study, we aimed to investigate the role of TAK1 in modulating neuroinflammation in the rd10 mouse model of human RP. We found that TAK1 was upregulated in the retina of rd10 mice and was especially over‐activated in the microglia which migrated to the outer nuclear layer where the degenerating photoreceptors resided. By genetic manipulation, we specifically deleted TAK1 from microglia and revealed that homozygous TAK1‐deficiency resulted in microglial cell death in the retina which could be accelerated by Cx3cr1‐ deficiency. Our in vitro experiments indicate that RIPK1's upregulation may contribute to microglia apoptosis induced by homozygous TAK1‐deficiency in the retina. On the other hand, heterozygous TAK1‐deficiency did not affect microglia viability in the retina. Moreover, heterozygous TAK1‐deficiency dramatically alleviated microglia activation during photoreceptor degeneration in rd10 mice through decreasing microglial proliferation and microglial migration to the outer nuclear layer. Our in vitro experiments suggest that AP‐1's upregulation may contribute to the anti‐inflammatory effect after heterozygous TAK1‐dificency is induced in retinal microglia of rd10 mice. In these two kinds of conditions, microglia‐specific homozygous and heterozygous TAK1‐deficiency, the proinflammatory factors were dramatically downregulated and photoreceptors' structure and function were significantly preserved in rd10 mice retina. Furthermore, pharmacological inhibition of TAK1 recapitulated the beneficial effect of heterozygous TAK1‐deficiency in microglia in rd10 mice retina. Taken together, our findings demonstrate that TAK1 supports microglia survival in the retina and that TAK1's upregulation in microglia contributes to the activation of microglia and subsequently contributes to neuroinflammation and photoreceptor degeneration in rd10 mice retina. Our study provides evidence that TAK1 can be a potential target for RP treatment.