LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis
LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis
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LRRK2 在维持肺稳态和预防肺纤维化发展中发挥重要作用
DOI：
10.1073/pnas.2106685118
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发表时间：
2021-08-31
影响因子：
11.1
通讯作者：
Wu, Li
中科院分区：
文献类型：
--
作者：
Tian, Yujie;Lv, Jiaoyan;Wu, Li
意义 肺纤维化是许多肺部疾病常见的最终结局，其发生可能与肺稳态紊乱、肺功能改变密切相关。在这项研究中，我们发现富含亮氨酸的重复激酶 2 (LRRK2) 是博来霉素诱导的肺纤维化背景下肺泡 II 型上皮 (AT2) 协调肺部反应的关键分子。我们的结果表明，LRRK2 通过防止 AT2 细胞功能障碍和随后的 CCL2/CCR2 轴依赖性巨噬细胞介导的促纤维化反应来抑制进行性肺纤维化。我们的研究强调了 LRRK2 在维持肺稳态和预防纤维化肺疾病中的重要生物学功能，从而为开发临床治疗策略提供了潜在的靶点。肺稳态的扰动通常与进行性和致命的呼吸系统疾病有关，例如肺纤维化。富含亮氨酸重复激酶 2 (LRRK2) 在健康肺部高表达，但其在肺稳态和疾病中的功能仍然难以捉摸。在此，我们发现哺乳动物纤维化肺中 LRRK2 表达明显降低，并且 LRRK2 缺陷小鼠表现出博来霉素诱导的肺纤维化加剧。此外，我们证明，在博莱霉素治疗的小鼠中，肺泡 II 型上皮 (AT2) 细胞中 LRRK2 的表达显着降低，其缺陷导致 AT2 细胞严重功能障碍，其特征是自噬受损和细胞衰老加速。此外，LRRK2缺陷的AT2细胞通过CCL2/CCR2信号传导表现出更高的募集促纤维化巨噬细胞的能力，导致广泛的巨噬细胞相关的促纤维化反应和进行性肺纤维化。综上所述，我们的研究表明 LRRK2 在预防 AT2 细胞功能障碍和协调先天免疫反应以防止肺纤维化方面发挥着至关重要的作用。
Significance Pulmonary fibrosis is a common final outcome of many lung diseases, and its occurrence may be closely associated with the disturbance of lung homeostasis and with alterations in pulmonary function. In this study, we identified leucine-rich repeat kinase 2 (LRRK2) as a pivotal molecule in alveolar type II epithelial (AT2)–coordinated pulmonary responses in the context of bleomycin-induced pulmonary fibrosis. Our results demonstrated that LRRK2 restrained progressive pulmonary fibrosis by preventing AT2 cell dysfunction and the subsequent CCL2/CCR2 axis–dependent macrophage-mediated profibrotic responses. Our study highlights the important biological functions of LRRK2 in the maintenance of lung homeostasis and the prevention of fibrotic lung disease, thereby providing a potential target for developing clinical therapeutic strategies. Perturbation of lung homeostasis is frequently associated with progressive and fatal respiratory diseases, such as pulmonary fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in healthy lungs, but its functions in lung homeostasis and diseases remain elusive. Herein, we showed that LRRK2 expression was clearly reduced in mammalian fibrotic lungs, and LRRK2-deficient mice exhibited aggravated bleomycin-induced pulmonary fibrosis. Furthermore, we demonstrated that in bleomycin-treated mice, LRRK2 expression was dramatically decreased in alveolar type II epithelial (AT2) cells, and its deficiency resulted in profound dysfunction of AT2 cells, characterized by impaired autophagy and accelerated cellular senescence. Additionally, LRRK2-deficient AT2 cells showed a higher capacity of recruiting profibrotic macrophages via the CCL2/CCR2 signaling, leading to extensive macrophage-associated profibrotic responses and progressive pulmonary fibrosis. Taken together, our study demonstrates that LRRK2 plays a crucial role in preventing AT2 cell dysfunction and orchestrating the innate immune responses to protect against pulmonary fibrosis.