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Title: ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis
Authors: Lam, TYW 
Nguyen, N 
Peh, HY 
Shanmugasundaram, M
Chandna, R 
Tee, JH 
Ong, CB
Hossain, MZ 
Venugopal, S 
Zhang, T
Xu, S
Qiu, T
Kong, WT 
Chakarov, S
Srivastava, S 
Liao, W 
Kim, JS
Teh, M 
Ginhoux, F
Wong, WSF 
Ge, R 
Keywords: ISM1
alveolar macrophages
cell surface GRP78
chronic obstructive pulmonary disease
Alveolar Epithelial Cells
Bronchoalveolar Lavage Fluid
Disease Models, Animal
Endoplasmic Reticulum Chaperone BiP
Intercellular Signaling Peptides and Proteins
Macrophages, Alveolar
Mice, Inbred BALB C
Pulmonary Disease, Chronic Obstructive
Pulmonary Emphysema
Issue Date: 25-Jan-2022
Publisher: Proceedings of the National Academy of Sciences
Citation: Lam, TYW, Nguyen, N, Peh, HY, Shanmugasundaram, M, Chandna, R, Tee, JH, Ong, CB, Hossain, MZ, Venugopal, S, Zhang, T, Xu, S, Qiu, T, Kong, WT, Chakarov, S, Srivastava, S, Liao, W, Kim, JS, Teh, M, Ginhoux, F, Wong, WSF, Ge, R (2022-01-25). ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis. Proceedings of the National Academy of Sciences of the United States of America 119 (4) : e2019161119-. ScholarBank@NUS Repository.
Abstract: 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.
Source Title: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 00278424
DOI: 10.1073/pnas.2019161119
Appears in Collections:Staff Publications

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