Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation
Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation
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DOI：
10.1111/all.15210
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发表时间：
2022-01-12
期刊：
影响因子：
12.4
通讯作者：
Zhang, Yaguang
中科院分区：
文献类型：
--
作者：
Huang, Yuying;Li, Xuezhen;Zhang, Yaguang
背景生物体具有协调的凝血和免疫系统。虽然在哮喘中已经报道了炎症和止血之间的联系，但其相互作用机制尚未完全阐明。在这里，我们研究了哺乳动物免疫和凝血系统之间的直接联系。方法采用蛋白酶或抗原鼻内给药诱导小鼠气道炎症模型，同时给予凝血酶抑制剂或不给予凝血酶抑制剂。研究了凝血酶及其抑制剂对白细胞介素（IL）-33（IL-33）的影响。收集来自哮喘患者的外周血单核细胞（PBMC）和血浆以验证凝血酶与第2组先天淋巴细胞（ILC 2）之间的相关性。结果低分子量肝素（LMWH，一种凝血酶的间接抑制剂）通过抑制IL-33的裂解而抑制木瓜蛋白酶和真菌诱导的小鼠2型免疫应答。在检查潜在的凝血酶蛋白酶共有位点后，我们发现IL-33在特定氨基酸（R48和R106）处被凝血酶直接切割，以产生具有有效生物活性的成熟形式的IL-33。此外，我们发现比伐卢定TFA（凝血酶的直接抑制剂）抑制多种2型炎症反应，如屋尘螨（HDM）和卵清蛋白（OVA）介导的肺部炎症模型。我们发现，哮喘患者血浆凝血酶-抗凝血酶复合物（TATc）水平与哮喘患者外周血单个核细胞（PBMC）中IL-33应答组2先天性淋巴细胞（ILC 2）的数量和功能呈正相关。结论凝血酶抑制剂可通过调节IL-33成熟调节ILC 2s的表达而有效治疗肺部炎症，提示凝血酶靶向治疗过敏性疾病是一种潜在的治疗方法。
Background Organisms have orchestrated coagulation and immune systems. Although a link between inflammation and haemostasis has been reported in asthma, the interaction mechanism has not been completely elucidated. Here, we investigated the direct link between the mammalian immune and coagulation systems. Methods Mice were administered protease or antigens intranasally to induce airway inflammation with or without thrombin inhibitors treatment. The effects of thrombin and its inhibitors on interleukin (IL)-33 were investigated both in vivo and in vitro. Peripheral blood mononuclear cells (PBMCs) and plasma from asthma patients are collected to verify the correlation between thrombin and group 2 innate lymphocytes (ILC2s). Results Low-molecular-weight heparin (LMWH, an indirect inhibitor of thrombin) restrained both papain- and fungus-induced type 2 immune responses in mice by inhibiting IL-33 cleavage. Upon examining the potential thrombin protease consensus sites, we found that IL-33 was directly cleaved by thrombin at specific amino acids (R48 and R106) to generate a mature form of IL-33 with potent biological activity. In addition, we found that bivalirudin TFA (a direct inhibitor of thrombin) inhibited a variety of type 2 inflammatory responses, such as those in house dust mite (HDM)- and ovalbumin (OVA)-mediated pulmonary inflammation models. We found that plasma thrombin-antithrombin complex (TATc) levels in asthma patients were positively associated with the number and function of IL-33-responder group 2 innate lymphocytes (ILC2s) among peripheral blood mononuclear cells (PBMCs) from asthma patients. Conclusion The data suggested that thrombin inhibitors administration could be effective in treating lung inflammation by regulating ILC2s via IL-33 maturation, indicating that targeting thrombin is a potential way to treat allergic diseases.