Hirano Taizo, Koarai Akira, Ohkouchi Shinya, Sugiura Hisatoshi, Kurosawa Hajime
Department of Occupational Health, Graduate School of Medical Sciences, Tohoku University Graduate School of Medicine, Sendai, JPN.
Department of Respiratory Medicine, Sendai City Hospital, Sendai, JPN.
Cureus. 2025 May 20;17(5):e84488. doi: 10.7759/cureus.84488. eCollection 2025 May.
Introduction Serine proteases play a critical role in the augmented release and cleavage of IL-33, leading to the expansion of group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) airway inflammation. However, the protective regulation of protease-dependent interleukin-33 (IL-33) activation remains poorly understood. Therefore, we investigated the role of secretory leukocyte protease inhibitor (SLPI), as a serine protease inhibitor, in this protective regulation and aimed to clarify its contribution to type 2 immunity. Methods We evaluated the role of SLPI in the extract-induced expansion of ILC2s and Th2-type airway inflammation via IL-33, using three models: SLPI-deficient mice, an in vivo SLPI knockdown model with shRNA, and an in vitro model utilizing primary human bronchial epithelial cells (HBECs) exposed to extract under various conditions, including plasmid transfection. Results We showed that two mouse models of downregulation ofgene expression augmented extract-induced release of IL-33 and the expansion of ILC2s, together with Th2 airway inflammation. Furthermore, two treatment models using KO mice, administration of a serine protease inhibitor, bovine pancreatic trypsin inhibitor, or anti-IL-33 antibody, attenuated Th2 airway inflammation. In two in vitro experiments, SLPI, as a serine protease inhibitor, prevented both the release of IL-33 from HBECs and the cleavage of full-length IL-33 to shorter mature forms by neutrophil elastase. Discussion These findings suggest that SLPI functions as a key serine protease inhibitor in regulating IL-33-mediated type 2 immune responses. Low SLPI levels may contribute to the pathogenesis of asthma by promoting Th2 inflammation, highlighting SLPI as a potential therapeutic target in patients with low SLPI expression.
引言 丝氨酸蛋白酶在白细胞介素-33（IL-33）的释放增加和裂解过程中发挥关键作用，导致2型固有淋巴细胞（ILC2s）扩增和辅助性T细胞2（Th2）介导的气道炎症。然而，蛋白酶依赖性白细胞介素-33（IL-33）激活的保护性调节机制仍知之甚少。因此，我们研究了分泌型白细胞蛋白酶抑制剂（SLPI）作为一种丝氨酸蛋白酶抑制剂在这种保护性调节中的作用，旨在阐明其对2型免疫的贡献。方法 我们使用三种模型评估了SLPI在提取物诱导的ILC2s扩增和通过IL-33介导的Th2型气道炎症中的作用：SLPI基因缺陷小鼠、体内使用短发夹RNA（shRNA）的SLPI敲低模型以及体外模型，该模型利用原代人支气管上皮细胞（HBECs）在包括质粒转染在内的各种条件下暴露于提取物。结果 我们发现，两种基因表达下调的小鼠模型增强了提取物诱导的IL-33释放、ILC2s扩增以及Th2气道炎症。此外，两种使用基因敲除小鼠的治疗模型，即给予丝氨酸蛋白酶抑制剂牛胰蛋白酶抑制剂或抗IL-33抗体，减轻了Th2气道炎症。在两项体外实验中，作为丝氨酸蛋白酶抑制剂的SLPI既能阻止HBECs释放IL-33，又能防止中性粒细胞弹性蛋白酶将全长IL-33裂解为较短的成熟形式。讨论 这些发现表明，SLPI在调节IL-33介导的2型免疫反应中起关键丝氨酸蛋白酶抑制剂作用。低水平的SLPI可能通过促进Th2炎症而导致哮喘发病机制，这突出了SLPI作为SLPI表达低的患者潜在治疗靶点的地位。
