HMGB1-pCTS-L轴的药理学干预改善炎症性疾病
Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases.
摘要(中文译文)
失调的炎症以炎症介质的失控释放为特征，是众多炎症性疾病发病机制的核心，包括急性脓毒症和慢性类风湿关节炎（RA）。尽管RA的治疗取得了进展，但当前抗炎治疗的局限性——如广泛免疫抑制和部分疗效——凸显了亟需新型干预手段。本综述批判性地审视了高迁移率族蛋白B1（HMGB1）和前组织蛋白酶-L（pCTS-L）在失调性炎症中的致病作用，这些作用由其与Toll样受体4（TLR4）和晚期糖基化终产物受体（RAGE）的相互作用所介导。至关重要的是，我们重点阐述了新建立的HMGB1-pCTS-L轴，其中HMGB1直接上调pCTS-L的表达和释放。该轴启动了一个延迟但持续的炎症环路，可能主要激活更为持久的非经典NF-κB通路。此外，我们探讨了四连接素（TN）——一种内源性HMGB1结合蛋白——的复杂作用，它抑制HMGB1释放，但 paradoxically 促进HMGB1诱导的细胞焦亡。利用这一复杂性，我们介绍了源自TN的P2-1肽，作为HMGB1-pCTS-L轴的高度特异性抑制剂。该肽结合HMGB1，阻止其与RAGE结合及随后的巨噬细胞焦亡，而不广泛抑制初始炎症级联反应。它还能特异性抑制HMGB1诱导的pCTS-L表达和释放，即使在延迟治疗的情况下也能改善脓毒症和RA。其“疾病触发”机制——仅在病理部位选择性靶向细胞外HMGB1——有望提高安全性和精确性。本综述将HMGB1-pCTS-L轴定位为一个关键且具有治疗可操作性的通路，抑制HMGB1和pCTS-L的抗体及模拟肽代表了有望用于一系列炎症疾病的下一代干预手段。
Abstract
Dysregulated inflammation, characterized by the uncontrolled release of inflammatory mediators, is central to the pathogenesis of numerous inflammatory diseases, including acute sepsis and chronic rheumatoid arthritis (RA). Despite therapeutic advances in RA, limitations of current anti-inflammatory treatments-such as broad immunosuppression and partial efficacy-highlight an urgent need for novel interventions. This review critically examines the pathogenic roles of High Mobility Group Box 1 (HMGB1) and procathepsin-L (pCTS-L) in dysregulated inflammation, mediated by their interactions with Toll-like receptor 4 (TLR4) and the Receptor for Advanced Glycation End Products (RAGE). Crucially, we highlight the newly established HMGB1-pCTS-L axis, in which HMGB1 directly upregulates pCTS-L expression and release. This axis initiates a delayed yet sustained inflammatory loop, which may predominantly activate the more enduring non-canonical NF-κB pathway. Furthermore, we explore the intricate role of tetranectin (TN), an endogenous HMGB1-binding protein, which inhibits HMGB1 release but paradoxically facilitates HMGB1-induced pyroptosis. Leveraging this complexity, we introduce the TN-derived P2-1 peptide as a highly specific inhibitor of the HMGB1-pCTS-L axis. This peptide binds HMGB1 to prevent its RAGE engagement and subsequent macrophage pyroptosis, without broadly suppressing initial inflammatory cascades. It also specifically inhibits HMGB1-induced pCTS-L expression and release, ameliorating both sepsis and RA even with delayed treatment. Its "disease-triggered" mechanism, selectively targeting extracellular HMGB1 only at pathological sites, promises enhanced safety and precision. This review positions the HMGB1-pCTS-L axis as a critical and therapeutically tractable pathway, with HMGB1- and pCTS-L-inhibiting antibodies and mimetic peptides representing promising next-generation interventions for a spectrum of inflammatory diseases.
如何引用
AMA
Weiqiang Chen, Jianhua Li, Xiaoling Qiang, Li Lou, Cassie Shu Zhu, Meihong Deng, et al. Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1843251.
APA
Weiqiang Chen, Jianhua Li, Xiaoling Qiang, Li Lou, Cassie Shu Zhu, Meihong Deng, et al (2026). Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1843251
GB/T 7714
Weiqiang Chen, Jianhua Li, Xiaoling Qiang, Li Lou, Cassie Shu Zhu, Meihong Deng, et al. Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1843251.
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