Mast cell chymase affects the functional properties of primary human airway fibroblasts: Implications for asthma

• Published in: Journal of allergy and clinical immunology 2022-02, Vol.149 (2), p.718-727
• Main Authors: Zhao, Xinran O., Lampinen, Maria, Rollman, Ola, Sommerhoff, Christian P., Paivandy, Aida, Pejler, Gunnar
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; asthma; Asthma - etiology; Cells, Cultured; chymase; Chymases - toxicity; Collagen Type I - metabolism; fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Lung - drug effects; Lung - metabolism; Lung - pathology; Mast cells; Mast Cells - enzymology; Mast Cells - physiology; Transcriptome; tryptase; Tryptases - toxicity
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2021.07.020

Mast cells (MCs) have a profound impact on allergic asthma. Under such conditions, MCs undergo degranulation, resulting in the release of exceptionally large amounts of MC-restricted proteases. However, the role of these proteases in asthma is only partially understood. We sought to test our hypothesis that MC proteases can influence the functionality of human lung fibroblasts (HLFs). Primary HLFs were treated with MC chymase or tryptase, followed by assessment of parameters related to fibroblast function. HLFs underwent major morphologic changes in response to chymase, showing signs of cellular contraction, but were refractory to tryptase. However, no effects of chymase on HLF viability or proliferation were seen. Chymase, but not tryptase, had a major impact on the output of extracellular matrix–associated compounds from the HLFs, including degradation of fibronectin and collagen-1, and activation of pro–matrix metalloprotease 2. Further, chymase induced the release of various chemotactic factors from HLFs. In line with this, conditioned medium from chymase-treated HLFs showed chemotactic activity on neutrophils. Transcriptome analysis revealed that chymase induced a proinflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects. Chymase, but not tryptase, has a major impact on the phenotype of primary airway fibroblasts by modifying their output of extracellular matrix components and by inducing a proinflammatory phenotype.