Journal of Inflammation Research (Jun 2024)
VISTA Deficiency Exacerbates the Development of Pulmonary Fibrosis by Promoting Th17 Differentiation
Abstract
Haiping Xie,1,* Xuexin Zhong,1,* Junlin Chen,2 Shuang Wang,1 Yuefang Huang,2 Niansheng Yang1 1Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 2Department of Pediatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Niansheng Yang, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, 510080, People’s Republic of China, Tel +86-20-87755766 ext 8150, Email [email protected]: Interstitial lung disease (ILD), characterized by pulmonary fibrosis (PF), represents the end-stage of various ILDs. The immune system plays an important role in the pathogenesis of PF. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is an immune checkpoint with immune suppressive functions. However, its specific role in the development of PF and the underlying mechanisms remain to be elucidated.Methods: We assessed the expression of VISTA in CD4 T cells from patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Spleen cells from wild-type (WT) or Vsir−/− mice were isolated and induced for cell differentiation in vitro. Additionally, primary lung fibroblasts were isolated and treated with interleukin-17A (IL-17A). Mice were challenged with bleomycin (BLM) following VISTA blockade or Vsir knockout. Moreover, WT or Vsir−/− CD4 T cells were transferred into Rag1−/− mice, which were then challenged with BLM.Results: VISTA expression was decreased in CD4 T cells from patients with CTD-ILD. Vsir deficiency augmented T-helper 17 (Th17) cell differentiation in vitro. Furthermore, IL-17A enhanced the production of inflammatory cytokines, as well as the differentiation and migration of lung fibroblasts. Both VISTA blockade and knockout of Vsir increased the percentage of IL-17A-producing Th17 cells and promoted BLM-induced PF. In addition, mice receiving Vsir−/− CD4 T cells exhibited a higher percentage of Th17 cells and more severe PF compared to those receiving WT CD4 T cells.Conclusion: These findings demonstrate the significant role of VISTA in modulating the development of PF by controlling Th17 cell differentiation. These insights suggest that targeting VISTA could be a promising therapeutic strategy for PF. Keywords: VISTA, lung fibrosis, Th17 cells, IL-17A, fibroblast
