2. Academic Validation
  3. HMGB2 causes photoreceptor death via down-regulating Nrf2/HO-1 and up-regulating NF-κB/NLRP3 signaling pathways in light-induced retinal degeneration model

HMGB2 causes photoreceptor death via down-regulating Nrf2/HO-1 and up-regulating NF-κB/NLRP3 signaling pathways in light-induced retinal degeneration model

  • Free Radic Biol Med. 2022 Mar;181:14-28. doi: 10.1016/j.freeradbiomed.2022.01.018.
Yumeng Zhang 1,  Zhenzhen Zhao 1,  Xiaohuan Zhao 1,  Hai Xie 2,  Chaoyang Zhang 1,  Xiaodong Sun 3,  Jingfa Zhang 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China.
  • 2 Tongji Eye Institute, Department of Regenerative Medicine, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China.
  • 3 Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China. Electronic address: [email protected].
  • 4 Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China. Electronic address: [email protected].
PMID: 35091064 DOI: 10.1016/j.freeradbiomed.2022.01.018
Abstract

In the pathogenesis of retinal degenerative diseases, oxidative stress is a key driver leading to photoreceptor death and eventually vision loss. Currently, there are no effective therapies available to rescue photoreceptors in these diseases. High-mobility group box 2 (HMGB2), a pro-inflammatory factor and damage-associated molecular patterns (DAMPs), has been proven to mediate various inflammatory diseases, but its role in retinal degenerative diseases, especially in retinal inflammation and photoreceptor degeneration, still remains unknown. In this study, we assessed the localization and function of HMGB2 under oxidative stress and explored the underlying mechanisms in a mouse model of light-induced retinal damage (LIRD). The results showed that increased oxidative stress, the photoreceptors death, as well as the pyroptosis-related proteins were evidenced in mice retina after LIGHT exposure. HMGB2 protein was predominantly expressed in the outer nuclear layer (ONL), which was translocated to the cytoplasm and released after injury. The mechanistic effect of HMGB2 was studied in the 661w cell line treated with H2O2, showing that exogenous recombinant HMGB2 protein reduced the expressions of the antioxidant protein nuclear erythroid factor 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1), and induced NF-κB/NLRP3 signaling pathway. HMGB2 knockdown increased cell viability, up-regulated the expressions of Nrf2 and HO-1, down-regulated the expressions of pyroptosis-related proteins in H2O2-treated 661w cells; and also prevented photoreceptors loss and maintained ONL in mice model of LIRD. The present study proposed HMGB2 as a potential therapeutic target for treatment of retinal degenerative diseases.

Keywords

HMGB2; Oxidative stress; Photoreceptor; Pyroptosis; Retinal degeneration.

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