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Updated: May 29, 2026
Transpupillary Two-Photon In Vivo Imaging of the Mouse Retina
Published on: February 13, 2021
TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in
Rong Li1, Jun-Qi Fan1, Bin Lin1,2
1School of Optometry, The Hong Kong Polytechnic University, Hong Kong, China.
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 of Tpm1 attenuated 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) Tpm1-Apoe/Fabp5 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.
Insights
Tropomyosin 1 (TPM1) drives neuroinflammation in retinitis pigmentosa (RP) by linking cytoskeletal dysfunction to immunometabolic collapse. Targeting TPM1, particularly the LGALS9/CD45 axis, offers a novel therapeutic strategy for RP.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Retinitis pigmentosa (RP) is the leading inherited retinal disease causing photoreceptor loss.
- Neuroinflammation driven by microglia exacerbates RP, but its mechanisms are unclear.
Purpose of the Study:
- To identify novel regulators of neuroinflammation in RP.
- To elucidate the role of tropomyosin 1 (TPM1) in RP pathogenesis.
Main Methods:
- Integrated multiomics profiling in rd10 mice.
- Genetic manipulation of Tpm1 (ablation and overexpression).
- Analysis of molecular signaling pathways (AP-1, MAPK, SASP, lipid metabolism, LGALS9/CD45).
Main Results:
- TPM1 was identified as a key cytoskeletal-immune regulator in RP.
- Tpm1 ablation reduced microglial reactivity and preserved vision.
- TPM1 overexpression triggered self-reinforcing inflammation via four interconnected axes, including AP-1 activation, SASP induction, lipid accumulation, and LGALS9/CD45-mediated signaling.
- These pathways contribute to a self-sustaining neurodegeneration cycle.
Conclusions:
- TPM1 is a central driver of sustained neuroinflammation and immunometabolic dysfunction in RP.
- Targeting TPM1, especially the LGALS9/CD45 axis, presents a promising therapeutic avenue to disrupt inflammatory cycles and preserve retinal homeostasis.
