Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China.
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
Biochim Biophys Acta Mol Basis Dis. 2021 May 1;1867(5):166077. doi: 10.1016/j.bbadis.2021.166077. Epub 2021 Jan 27.
Idiopathic pulmonary fibrosis (IPF) is a lethal and agnogenic interstitial lung disease, which has limited therapeutic options. Recently, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome has been demonstrated as an important contributor to various fibrotic diseases following its persistent activation. However, the role of NLRP3 inflammasome in pulmonary fibrogenesis still needs to be further clarified. Here, we found that the activation of the NLRP3 inflammasome was raised in fibrotic lungs. In addition, the NLRP3 inflammasome was found to be activated in alveolar epithelial cells (AECs) in the lung tissue of both IPF patients and pulmonary fibrosis mouse models. Further research revealed that epithelial cells, following activation of the NLRP3 inflammasome, could induce the myofibroblast differentiation of lung-resident mesenchymal stem cells (LR-MSCs). In addition, inhibiting the activation of the NLRP3 inflammasome in epithelial cells promoted the expression of dickkopf-1 (DKK1), a secreted Wnt antagonist. DKK1 was capable of suppressing the profibrogenic differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis. In conclusion, this study not only provides a further in-depth understanding of the pathogenesis of pulmonary fibrosis, but also reveals a potential therapeutic strategy for disorders associated with pulmonary fibrosis.
特发性肺纤维化（IPF）是一种致命的、进行性的间质性肺疾病，其治疗选择有限。最近，NOD、LRR 和 pyrin 结构域包含 3（NLRP3）炎性小体被证明是各种纤维化疾病的一个重要贡献者，因为它持续激活。然而，NLRP3 炎性小体在肺纤维化发病机制中的作用仍需进一步阐明。在这里，我们发现纤维化肺中 NLRP3 炎性小体的激活增加了。此外，在 IPF 患者和肺纤维化小鼠模型的肺组织中发现 NLRP3 炎性小体在肺泡上皮细胞（AEC）中被激活。进一步的研究表明，上皮细胞在 NLRP3 炎性小体激活后，可以诱导肺驻留间充质干细胞（LR-MSCs）的肌成纤维细胞分化。此外，抑制上皮细胞中 NLRP3 炎性小体的激活可促进 Wnt 拮抗剂分泌 dickkopf-1（DKK1）的表达。DKK1 能够抑制 LR-MSCs 的促纤维化分化和博来霉素诱导的肺纤维化。总之，这项研究不仅为肺纤维化的发病机制提供了进一步的深入了解，而且为与肺纤维化相关的疾病提供了一种潜在的治疗策略。
