TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in retinitis pigmentosa
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Retinitis pigmentosa (RP), the most prevalent inherited retinal degeneration, features progressive photoreceptor loss with no approved disease-modifying therapies. While microglia-driven neuroinflammation accelerates RP progression, its sustaining mechanisms remain elusive. Through integrated multiomics profiling of retinal degeneration 10 (rd10) mice, we identify tropomyosin 1 (TPM1) as a previously unrecognized cytoskeletal-immune regulator orchestrating spatial neuroinflammation in RP. Genetic ablation ofattenuated microglial reactivity and preserved vision, whereas overexpression triggered self-reinforcing inflammation via four interlocked axes: (i) TPM1-mediated activator protein-1 (AP-1) hyperactivation initiates senescence-associated secretory phenotype (SASP) through mitogen-activated protein kinase (MAPK) kinase/extracellular signal–regulated kinase 3–dependent MAPK signaling; (ii) SASP subsequently mediates reduced phagocytosis; (iii)axis disruption precipitates lipid droplet accumulation with cholesterol crystallization; (iv) galectin-9 (LGALS9)/CD45-mediated intermicroglial signaling propagates inflammatory signals across the retina. Our work redefines TPM1 as a linchpin in self-sustaining neurodegeneration cycles, where cytoskeletal dysfunction fuels immunometabolic collapse. These findings unveil precision therapeutic strategies targeting TPM1 hubs—notably the LGALS9/CD45 axis—to disrupt inflammatory cycles while preserving retinal homeostasis. TPM1 drives RP ne
Abstract
Retinitis pigmentosa (RP), the most prevalent inherited retinal degeneration, features progressive photoreceptor loss with no approved disease-modifying therapies. While microglia-driven neuroinflammation accelerates RP progression, its sustaining mechanisms remain elusive. Through integrated multiomics profiling of retinal degeneration 10 (rd10) mice, we identify tropomyosin 1 (TPM1) as a previously unrecognized cytoskeletal-immune regulator orchestrating spatial neuroinflammation in RP. Genetic ablation ofattenuated microglial reactivity and preserved vision, whereas overexpression triggered self-reinforcing inflammation via four interlocked axes: (i) TPM1-mediated activator protein-1 (AP-1) hyperactivation initiates senescence-associated secretory phenotype (SASP) through mitogen-activated protein kinase (MAPK) kinase/extracellular signal–regulated kinase 3–dependent MAPK signaling; (ii) SASP subsequently mediates reduced phagocytosis; (iii)axis disruption precipitates lipid droplet accumulation with cholesterol crystallization; (iv) galectin-9 (LGALS9)/CD45-mediated intermicroglial signaling propagates inflammatory signals across the retina. Our work redefines TPM1 as a linchpin in self-sustaining neurodegeneration cycles, where cytoskeletal dysfunction fuels immunometabolic collapse. These findings unveil precision therapeutic strategies targeting TPM1 hubs—notably the LGALS9/CD45 axis—to disrupt inflammatory cycles while preserving retinal homeostasis. TPM1 drives RP neurodegeneration via cytoskeletal-immune networks, and targeting TPM1/LGALS9-CD45 preserves vision. teaser