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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 4; p. 1
• Main Authors: Lam, Terence Y W, Nguyen, Ngan, Peh, Hong Yong, Shanmugasundaram, Mahalakshmi, Chandna, Ritu, Tee, Jong Huat, Ong, Chee Bing, Hossain, Md Zakir, Venugopal, Shruthi, Zhang, Tianyi, Xu, Simin, Qiu, Tao, Kong, Wan Ting, Chakarov, Svetoslav, Srivastava, Supriya, Liao, Wupeng, Kim, Jin-Soo, Teh, Ming, Ginhoux, Florent, Fred Wong, W S, Ge, Ruowen
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.01.2022
• Subjects: Alveolar Epithelial Cells - metabolism; Alveoli; Animals; Apoptosis; Apoptosis - immunology; Biological Sciences; Bronchoalveolar Lavage Fluid - immunology; Cell surface; Chronic obstructive pulmonary disease; Cigarette smoke; Disease Models, Animal; Emphysema; Endoplasmic Reticulum Chaperone BiP - metabolism; Endoplasmic Reticulum Chaperone BiP - physiology; Female; Heterogeneity; Homeostasis; Immune system; Inflammation; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - physiology; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - physiology; Male; Mice; Mice, Inbred BALB C; Nicotiana - adverse effects; Obstructive lung disease; Phagocytosis - physiology; Phenotypes; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Emphysema - metabolism; Respiratory function; Smoke - adverse effects; Smoking - adverse effects; Trachea; apoptosis; ISM1; cell surface GRP78; alveolar macrophages; chronic obstructive pulmonary disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2019161119

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 ( ) 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 csGRP78 AMs are expanded in mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78 AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78 AMs in both 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.