ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis

促炎细胞因子 慢性阻塞性肺病 肺泡巨噬细胞 细胞凋亡 免疫学 巨噬细胞 免疫系统 炎症 生物 医学 癌症研究 平衡 内科学 生物化学 体外
作者
Terence Yin Weng Lam,Ngan Nguyen,Hong Yong Peh,Mahalakshmi Shanmugasundaram,Ritu Chandna,Tee Jong Huat,Chee Bing Ong,Md Zakir Hossain,Shruthi Venugopal,Tianyi Zhang,Simin Xu,Tao Qiu,Wan Ting Kong,Svetoslav Chakarov,Supriya Srivastava,Wupeng Liao,Jin‐Soo Kim,Ming Teh,Florent Ginhoux,W.S. Fred Wong
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:119 (4) 被引量:41
标识
DOI:10.1073/pnas.2019161119
摘要

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.
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