凝血酶分解IL-33并调节IL-33激活的过敏性肺部炎症
2022/07/19
摘要
背景：生物体有协调的凝血和免疫系统。尽管在哮喘病中已经报道了炎症和止血之间的联系，但相互作用的机制还没有完全阐明。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：在有或没有凝血酶抑制剂治疗的情况下，经鼻给予小鼠蛋白酶或抗原以诱导气道炎症。在体内和体外研究了凝血酶及其抑制剂对白细胞介素-33（IL-33）的影响。收集了哮喘患者的外周血单核细胞（PBMCs）和血浆，以验证凝血酶与2型固有淋巴细胞（ILC2s）之间的相关性
结果：低分子肝素（LMWH，一种凝血酶的间接抑制剂）通过抑制IL-33的裂解，抑制了木瓜蛋白酶和真菌诱导的小鼠2型免疫反应。在检查了潜在的凝血酶-蛋白酶共识位点后，我们发现IL-33在特定的氨基酸（R48和R106）处被凝血酶直接裂解，生成具有强大生物活性的成熟形式IL-33。此外，我们发现比伐卢定TFA（一种直接的凝血酶抑制剂）可以抑制多种2型炎症反应，如室内尘螨（HDM）和卵清蛋白（OVA）介导的肺部炎症模型。我们发现，哮喘患者血浆中的凝血酶-抗凝血酶复合物（TATc）水平与哮喘患者外周血单核细胞（PBMCs）中IL-33应答者的2型固有淋巴细胞（ILC2s）的数量和功能呈正相关。
结论：数据表明，凝血酶抑制剂的给药可以通过IL-33的成熟来调节ILC2s，从而有效地治疗肺部炎症，表明靶向凝血酶是治疗过敏性疾病的一个潜在途径。
Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation
Huang, Y., Li, X., Zhu, L., Huang, C., Chen, W., Ling, Z., Zhu, S., Feng, X., Yi, C., Gu, W., Yan, C., Wang, J., Ma, L., Su, X., Dai, R., Shi, G., Sun, B., & Zhang, Y.
Abstract
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.
背景：生物体有协调的凝血和免疫系统。尽管在哮喘病中已经报道了炎症和止血之间的联系，但相互作用的机制还没有完全阐明。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：在有或没有凝血酶抑制剂治疗的情况下，经鼻给予小鼠蛋白酶或抗原以诱导气道炎症。在体内和体外研究了凝血酶及其抑制剂对白细胞介素-33（IL-33）的影响。收集了哮喘患者的外周血单核细胞（PBMCs）和血浆，以验证凝血酶与2型固有淋巴细胞（ILC2s）之间的相关性
结果：低分子肝素（LMWH，一种凝血酶的间接抑制剂）通过抑制IL-33的裂解，抑制了木瓜蛋白酶和真菌诱导的小鼠2型免疫反应。在检查了潜在的凝血酶-蛋白酶共识位点后，我们发现IL-33在特定的氨基酸（R48和R106）处被凝血酶直接裂解，生成具有强大生物活性的成熟形式IL-33。此外，我们发现比伐卢定TFA（一种直接的凝血酶抑制剂）可以抑制多种2型炎症反应，如室内尘螨（HDM）和卵清蛋白（OVA）介导的肺部炎症模型。我们发现，哮喘患者血浆中的凝血酶-抗凝血酶复合物（TATc）水平与哮喘患者外周血单核细胞（PBMCs）中IL-33应答者的2型固有淋巴细胞（ILC2s）的数量和功能呈正相关。
结论：数据表明，凝血酶抑制剂的给药可以通过IL-33的成熟来调节ILC2s，从而有效地治疗肺部炎症，表明靶向凝血酶是治疗过敏性疾病的一个潜在途径。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Allergy. 2022 Jul;77(7):2104-2120. DOI: 10.1111/all.15210)
(Allergy. 2022 Jul;77(7):2104-2120. DOI: 10.1111/all.15210)
Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation
Huang, Y., Li, X., Zhu, L., Huang, C., Chen, W., Ling, Z., Zhu, S., Feng, X., Yi, C., Gu, W., Yan, C., Wang, J., Ma, L., Su, X., Dai, R., Shi, G., Sun, B., & Zhang, Y.
Abstract
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.
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