{"title":"组织蛋白酶S:免疫系统疾病的关键药物靶点和信号中枢","authors":"Durga Geetha, Tom Skaria","doi":"10.1016/j.intimp.2025.114622","DOIUrl":null,"url":null,"abstract":"<div><div>The lysosomal cysteine protease cathepsin S supports host defence by promoting the maturation of MHC class-II proteins. In contrast, increased cathepsin S activity mediates tissue destructive immune responses in autoimmune and inflammatory diseases. Therefore, cathepsin S is a key target in drug discovery programs. Here, we critically reviewed the specific mechanisms by which cathepsin S mediates autoimmune and hyperinflammatory responses to identify new targets for therapeutic immunomodulation. To this end, we performed literature review utilizing PubMed, drug database of US FDA, European Medicines Agency and the Drug-Gene Interaction Database. Cathepsin S destroys T cell epitopes and reduces endogenous antigen diversity, impairing negative selection of autoreactive T cells that could recognize these epitopes. Moreover, cathepsin S critically regulates inflammatory disease severity by generating proinflammatory molecules (PAR-1, PAR-2, IL-36γ, Fractalkine, Endostatin, Ephrin-B2), inactivating anti-inflammatory mediators (SLPI) and degrading molecules involved in antimicrobial and immunomodulatory responses (surfactant protein-A, LL-37, beta-defensins), inter-endothelial/−epithelial barrier function, gene repair and energy homeostasis. These pathways could be targeted by repositioning of existing drugs. These findings suggest that inhibiting cathepsin S or a specific downstream target of cathepsin S by repositioning of existing drugs could be a promising strategy for treating autoimmune and inflammatory diseases. Current cathepsin S inhibitors in clinical trials face challenges, highlighting the need for innovative inhibitors that function effectively in various cellular compartments with differing pH levels, without targeting the shared catalytic site of cysteine cathepsins.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"155 ","pages":"Article 114622"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cathepsin S: A key drug target and signalling hub in immune system diseases\",\"authors\":\"Durga Geetha, Tom Skaria\",\"doi\":\"10.1016/j.intimp.2025.114622\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The lysosomal cysteine protease cathepsin S supports host defence by promoting the maturation of MHC class-II proteins. In contrast, increased cathepsin S activity mediates tissue destructive immune responses in autoimmune and inflammatory diseases. Therefore, cathepsin S is a key target in drug discovery programs. Here, we critically reviewed the specific mechanisms by which cathepsin S mediates autoimmune and hyperinflammatory responses to identify new targets for therapeutic immunomodulation. To this end, we performed literature review utilizing PubMed, drug database of US FDA, European Medicines Agency and the Drug-Gene Interaction Database. Cathepsin S destroys T cell epitopes and reduces endogenous antigen diversity, impairing negative selection of autoreactive T cells that could recognize these epitopes. Moreover, cathepsin S critically regulates inflammatory disease severity by generating proinflammatory molecules (PAR-1, PAR-2, IL-36γ, Fractalkine, Endostatin, Ephrin-B2), inactivating anti-inflammatory mediators (SLPI) and degrading molecules involved in antimicrobial and immunomodulatory responses (surfactant protein-A, LL-37, beta-defensins), inter-endothelial/−epithelial barrier function, gene repair and energy homeostasis. These pathways could be targeted by repositioning of existing drugs. These findings suggest that inhibiting cathepsin S or a specific downstream target of cathepsin S by repositioning of existing drugs could be a promising strategy for treating autoimmune and inflammatory diseases. Current cathepsin S inhibitors in clinical trials face challenges, highlighting the need for innovative inhibitors that function effectively in various cellular compartments with differing pH levels, without targeting the shared catalytic site of cysteine cathepsins.</div></div>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":\"155 \",\"pages\":\"Article 114622\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-04-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International immunopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1567576925006125\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576925006125","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
溶酶体半胱氨酸蛋白酶 cathepsin S 可促进 MHC II 类蛋白质的成熟,从而支持宿主防御。相反,在自身免疫性和炎症性疾病中,溶酶体半胱氨酸蛋白酶 S 活性的增加会介导组织破坏性免疫反应。因此,鲶鱼蛋白酶 S 是药物发现计划中的一个关键靶点。在此,我们认真回顾了鲶鱼蛋白酶 S 介导自身免疫和高炎症反应的具体机制,以确定治疗性免疫调节的新靶点。为此,我们利用 PubMed、美国 FDA 药物数据库、欧洲药品管理局和药物基因相互作用数据库进行了文献综述。酪蛋白酶 S 会破坏 T 细胞表位并减少内源性抗原的多样性,从而影响可识别这些表位的自反应 T 细胞的负选择。此外,酪蛋白酶 S 通过产生促炎分子(PAR-1、PAR-2、IL-36γ、Fractalkine、Endostatin、Ephrin-B2)、灭活抗炎介质(SLPI)和降解参与抗微生物和免疫调节反应的分子(表面活性蛋白-A、LL-37、β-防御素)、内皮/上皮间屏障功能、基因修复和能量平衡,对炎症疾病的严重程度起着至关重要的调节作用。可通过对现有药物进行重新定位来针对这些途径进行治疗。这些发现表明,通过对现有药物进行重新定位来抑制酪蛋白酶 S 或酪蛋白酶 S 的特定下游靶点,可能是治疗自身免疫性和炎症性疾病的一种很有前景的策略。目前正在进行临床试验的鲶鱼蛋白酶 S 抑制剂面临着挑战,这凸显了人们对创新抑制剂的需求,这种抑制剂能在 pH 值不同的各种细胞区室中有效发挥作用,而且不针对半胱氨酸鲶鱼蛋白的共同催化位点。
Cathepsin S: A key drug target and signalling hub in immune system diseases
The lysosomal cysteine protease cathepsin S supports host defence by promoting the maturation of MHC class-II proteins. In contrast, increased cathepsin S activity mediates tissue destructive immune responses in autoimmune and inflammatory diseases. Therefore, cathepsin S is a key target in drug discovery programs. Here, we critically reviewed the specific mechanisms by which cathepsin S mediates autoimmune and hyperinflammatory responses to identify new targets for therapeutic immunomodulation. To this end, we performed literature review utilizing PubMed, drug database of US FDA, European Medicines Agency and the Drug-Gene Interaction Database. Cathepsin S destroys T cell epitopes and reduces endogenous antigen diversity, impairing negative selection of autoreactive T cells that could recognize these epitopes. Moreover, cathepsin S critically regulates inflammatory disease severity by generating proinflammatory molecules (PAR-1, PAR-2, IL-36γ, Fractalkine, Endostatin, Ephrin-B2), inactivating anti-inflammatory mediators (SLPI) and degrading molecules involved in antimicrobial and immunomodulatory responses (surfactant protein-A, LL-37, beta-defensins), inter-endothelial/−epithelial barrier function, gene repair and energy homeostasis. These pathways could be targeted by repositioning of existing drugs. These findings suggest that inhibiting cathepsin S or a specific downstream target of cathepsin S by repositioning of existing drugs could be a promising strategy for treating autoimmune and inflammatory diseases. Current cathepsin S inhibitors in clinical trials face challenges, highlighting the need for innovative inhibitors that function effectively in various cellular compartments with differing pH levels, without targeting the shared catalytic site of cysteine cathepsins.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.