SIPA1L1 对 POAG 小梁网细胞外基质蛋白积累和细胞吞噬功能的影响。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-22 DOI:10.1172/jci.insight.174836
Chenyu Xu, Jiahong Wei, Dan Song, Siyu Zhao, Mingmin Hou, Yuchen Fan, Li Guo, Hao Sun, Tao Guo
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引用次数: 0

摘要

细胞外基质(ECM)蛋白在小梁网(TM)中积聚,导致房水外流阻力增加,从而导致高眼压,这是原发性开角型青光眼(POAG)的主要原因。根据我们的初步研究,参与组织纤维化的 RapGAP 蛋白超家族成员信号诱导增殖相关 1 样 1 蛋白(SIPA1L1)可能会通过影响 TM 的 ECM 代谢对 POAG 产生影响。本研究旨在证实这些发现,并确定 SIPA1L1 对人 TM(HTM)细胞中 ECM 变化和吞噬作用的影响及细胞机制。无标签定量蛋白质组学研究结果表明,TGFβ2处理可显著增加SIPA1L1在HTM细胞中的表达。POAG患者的房水和TM细胞中SIPA1L1的浓度高于对照组。在 HTM 细胞中,TGFβ2 增加了 SIPA1L1 的表达以及 ECM、RhoA 和 p-Cofilin1 的积累。si-SIPA1L1 可减少 TGFβ2 的影响。TGFβ2 通过聚合细胞骨架肌动蛋白丝来减少 HTM 细胞的吞噬作用,而 si-SIPA1L1 则通过分解肌动蛋白丝来增加吞噬作用。同时,单独过表达 SIPA1L1 与 TGFβ2 的效果相当。我们的研究表明,SIPA1L1 不仅能促进 ECM 的生成,还能通过减少吞噬作用抑制 ECM 的清除。以 SIPA1L1 降解为靶点可能成为治疗 POAG 的重要方法。
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Effects of SIPA1L1 on trabecular meshwork extracellular matrix protein accumulation and cellular phagocytosis in POAG.

Accumulation of extracellular matrix (ECM) proteins in trabecular meshwork (TM), which leads to increased outflow resistance of aqueous humor and consequently high intraocular pressure, is a major cause of primary open-angle glaucoma (POAG). According to our preliminary research, the RapGAP protein superfamily member, signal-induced proliferation-associated 1-like 1 protein (SIPA1L1), which is involved in tissue fibrosis, may have an impact on POAG by influencing ECM metabolism of TM. This study aims to confirm these findings and identify effects and cellular mechanisms of SIPA1L1 on ECM changes and phagocytosis in human TM (HTM) cells. Our results showed that the expression of SIPA1L1 in HTM cells was significantly increased by TGF-β2 treatment in label-free quantitative proteomics. The aqueous humor and TM cell concentration of SIPA1L1 in POAG patients was higher than that of control. In HTM cells, TGF-β2 increased expression of SIPA1L1 along with accumulation of ECM, RhoA, and p-cofilin 1. The effects of TGF-β2 were reduced by si-SIPA1L1. TGF-β2 decreased HTM cell phagocytosis by polymerizing cytoskeletal actin filaments, while si-SIPA1L1 increased phagocytosis by disassembling actin filaments. Simultaneously, overexpressing SIPA1L1 alone exhibited comparable effects to that of TGF-β2. Our studies demonstrate that SIPA1L1 not only promotes the production of ECM, but also inhibits its removal by reducing phagocytosis. Targeting SIPA1L1 degradation may become a significant therapy for POAG.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
期刊最新文献
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