Drake Li Y, Koloko Ngassie Maunick Lefin, Roos Benjamin B, Teske Jacob J, Prakash Y S
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States.
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Front Physiol. 2023 Jan 25;14:1064822. doi: 10.3389/fphys.2023.1064822. eCollection 2023.
Lung fibroblasts contribute to asthma pathology partly through modulation of the immune environment in the airway. Tumor necrosis factor-α (TNFα) expression is upregulated in asthmatic lungs. How asthmatic lung fibroblasts respond to TNFα stimulation and subsequently regulate immune responses is not well understood. Endoplasmic reticulum (ER) stress and unfolded protein responses (UPR) play important roles in asthma, but their functional roles are still under investigation. In this study, we investigated TNFα-induced cytokine production in primary lung fibroblasts from asthmatic vs. non-asthmatic human subjects, and downstream effects on type 2 immune responses. TNFα significantly upregulated IL-6, IL-8, C-C motif chemokine ligand 5 (CCL5), and thymic stromal lymphopoietin (TSLP) mRNA expression and protein secretion by lung fibroblasts. Asthmatic lung fibroblasts secreted higher levels of TSLP which promoted IL-33-induced IL-5 and IL-13 production by peripheral blood mononuclear cells. TNFα exposure enhanced expression of ER stress/UPR pathways in both asthmatic and non-asthmatic lung fibroblasts, especially inositol-requiring protein 1α in asthmatics. ER stress/UPR inhibitors decreased IL-6, CCL5, and TSLP protein secretion by asthmatic lung fibroblasts. Our data suggest that TNFα and lung fibroblasts form an important axis in asthmatic lungs to promote asthmatic inflammation that can be attenuated by inhibiting ER stress/UPR pathway.
肺成纤维细胞部分通过调节气道免疫环境对哮喘病理产生影响。肿瘤坏死因子-α（TNFα）在哮喘患者肺组织中的表达上调。目前尚不清楚哮喘患者的肺成纤维细胞如何对TNFα刺激作出反应并随后调节免疫反应。内质网（ER）应激和未折叠蛋白反应（UPR）在哮喘中起重要作用，但其功能作用仍在研究中。在本研究中，我们调查了TNFα诱导的哮喘患者与非哮喘患者原代肺成纤维细胞中细胞因子的产生，以及对2型免疫反应的下游影响。TNFα显著上调肺成纤维细胞中白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、C-C基序趋化因子配体5（CCL5）和胸腺基质淋巴细胞生成素（TSLP）的mRNA表达和蛋白分泌。哮喘患者的肺成纤维细胞分泌更高水平的TSLP，其促进外周血单核细胞产生由白细胞介素-33（IL-33）诱导的白细胞介素-5（IL-5）和白细胞介素-13（IL-13）。TNFα暴露增强了哮喘和非哮喘患者肺成纤维细胞中ER应激/UPR通路的表达，尤其是哮喘患者中的肌醇需求蛋白1α（IRE1α）。ER应激/UPR抑制剂减少了哮喘患者肺成纤维细胞中IL-6、CCL5和TSLP的蛋白分泌。我们的数据表明，TNFα和肺成纤维细胞在哮喘患者肺组织中形成一个重要轴，以促进哮喘炎症，而抑制ER应激/UPR通路可减轻这种炎症。
