Zhao Xinran O, Sommerhoff Christian P, Paivandy Aida, Pejler Gunnar
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Institute of Laboratory Medicine, University Hospital, Ludwig Maximilian University Munich, Munich, Gremany.
J Allergy Clin Immunol. 2022 Dec;150(6):1534-1544. doi: 10.1016/j.jaci.2022.05.028. Epub 2022 Jun 30.
Mast cells are implicated in the pathogenesis of asthma, but the underlying mechanisms are not fully elucidated. Under asthmatic conditions, mast cells can relocalize to the epithelial layer and may thereby affect the functional properties of the airway epithelial cells.
Activated mast cells release large quantities of proteases from their secretory granules, including chymase and tryptase. Here we investigated whether these proteases may affect airway epithelial cells.
Primary small airway epithelial cells were treated with tryptase or chymase, and the effects on epithelial cell viability, proliferation, migration, cytokine output, and transcriptome were evaluated.
Airway epithelial cells were relatively refractory to tryptase. In contrast, chymase had extensive effects on multiple features of the epithelial cells, with a particular emphasis on processes related to extracellular matrix (ECM) remodeling. These included suppressed expression of ECM-related genes such as matrix metalloproteinases, which was confirmed at the protein level. Further, chymase suppressed the expression of the fibronectin gene and also caused degradation of fibronectin released by the epithelial cells. Chymase was also shown to suppress the migratory capacity of the airway epithelial cells and to degrade the cell-cell contact protein E-cadherin on the epithelial cell surface.
Our findings suggest that chymase may affect the regulation of ECM remodeling events mediated by airway epithelial cells, with implications for the impact of mast cells in inflammatory lung diseases such as asthma.
肥大细胞与哮喘的发病机制有关，但其潜在机制尚未完全阐明。在哮喘状态下，肥大细胞可重新定位于上皮层，从而可能影响气道上皮细胞的功能特性。
活化的肥大细胞从其分泌颗粒中释放大量蛋白酶，包括糜蛋白酶和组织蛋白酶。在此，我们研究了这些蛋白酶是否会影响气道上皮细胞。
用组织蛋白酶或糜蛋白酶处理原代小气道上皮细胞，并评估其对上皮细胞活力、增殖、迁移、细胞因子分泌和转录组的影响。
气道上皮细胞对组织蛋白酶相对不敏感。相比之下，糜蛋白酶对上皮细胞的多个特征有广泛影响，尤其着重于与细胞外基质（ECM）重塑相关的过程。这些影响包括抑制基质金属蛋白酶等ECM相关基因的表达，这在蛋白质水平得到证实。此外，糜蛋白酶抑制纤连蛋白基因的表达，并导致上皮细胞释放的纤连蛋白降解。糜蛋白酶还被证明可抑制气道上皮细胞的迁移能力，并降解上皮细胞表面的细胞间接触蛋白E-钙黏蛋白。
我们的研究结果表明，糜蛋白酶可能影响气道上皮细胞介导的ECM重塑事件的调节，这对肥大细胞在哮喘等炎症性肺病中的作用具有重要意义。
