Nie Yunjuan, Zhai Xiaorun, Li Jiao, Sun Aijuan, Che Huilian, Christman John W, Chai Gaoshang, Zhao Peng, Karpurapu Manjula
Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
Department of Pathology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China.
Aging Dis. 2023 Dec 11. doi: 10.14336/AD.2022.1226.
Idiopathic pulmonary fibrosis (IPF) is a progressive and highly lethal inflammatory interstitial lung disease characterized by aberrant extracellular matrix deposition. Macrophage activation by cytokines released from repetitively injured alveolar epithelial cells regulates the inflammatory response, tissue remodeling, and fibrosis throughout various phases of IPF. Our previous studies demonstrate that nuclear factor of activated T cells cytoplasmic member 3 (NFATc3) regulates a wide array of macrophage genes during acute lung injury pathogenesis. However, the role of NFATc3 in IPF pathophysiology has not been previously reported. In the current study, we demonstrate that expression of NFATc3 is elevated in lung tissues and pulmonary macrophages in mice subjected to bleomycin (BLM)-induced pulmonary fibrosis and IPF patients. Remarkably, NFATc3 deficiency (NFATc3) was protective in bleomycin (BLM)-induced lung injury and fibrosis. Adoptive transfer of NFATc3 macrophages to NFATc3 mice restored susceptibility to BLM-induced pulmonary fibrosis. Furthermore, in vitro treatment with IL-33 or conditioned medium from BLM-treated epithelial cells increased production of CCL2 and CXCL2 in macrophages from NFATc3 but not NFATc3 mice. CXCL2 promoter-pGL3 Luciferase reporter vector showed accentuated reporter activity when co-transfected with the NFATc3 expression vector. More importantly, exogenous administration of recombinant CXCL2 into NFATc3 mice increased fibrotic markers and exacerbated IPF phenotype in BLM treated mice. Collectively, our data demonstrate, for the first time, that NFATc3 regulates pulmonary fibrosis by regulating CCL2 and CXCL2 gene expression in macrophages.
特发性肺纤维化（IPF）是一种进行性且极具致死性的炎症性间质性肺疾病，其特征为细胞外基质异常沉积。反复受损的肺泡上皮细胞释放的细胞因子激活巨噬细胞，在IPF的各个阶段调节炎症反应、组织重塑和纤维化。我们之前的研究表明，活化T细胞核因子细胞质成员3（NFATc3）在急性肺损伤发病机制中调节多种巨噬细胞基因。然而，NFATc3在IPF病理生理学中的作用此前尚未见报道。在本研究中，我们证明在博来霉素（BLM）诱导的肺纤维化小鼠和IPF患者的肺组织及肺巨噬细胞中，NFATc3的表达升高。值得注意的是，NFATc3缺陷（NFATc3 -/-）对博来霉素（BLM）诱导的肺损伤和纤维化具有保护作用。将NFATc3 +/+巨噬细胞过继转移至NFATc3 -/-小鼠可恢复其对BLM诱导的肺纤维化的易感性。此外，用IL - 33或BLM处理的上皮细胞的条件培养基进行体外处理，可增加NFATc3 +/+而非NFATc3 -/-小鼠巨噬细胞中CCL2和CXCL2的产生。CXCL2启动子 - pGL3荧光素酶报告载体与NFATc3表达载体共转染时，显示出增强的报告活性。更重要的是，向NFATc3 -/-小鼠外源给予重组CXCL2可增加纤维化标志物，并加重BLM处理小鼠的IPF表型。总体而言，我们的数据首次证明，NFATc3通过调节巨噬细胞中CCL2和CXCL2基因表达来调节肺纤维化。
