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

Augustine University, September 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 (Ism7') leads to increase in both AM number and functional heterogeneity, with enduring lung inflam-mation, 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 trig-gers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heteroge-neous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism7-/� 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 Ism7i and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apopto-sis, 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.

Automated summary

This study reveals the importance of alveolar macrophages (AMs) in maintaining lung homeostasis and their role in chronic obstructive pulmonary disease (COPD). The absence of IST1 protein leads to increased AM numbers and altered functions, resulting in lung inflammation and COPD-like symptoms. The study also identifies csGRP78high AMs as the primary targets of IST1-mediated apoptosis. Intratracheal delivery of recombinant IST1 shows potential as a therapeutic strategy for COPD by targeting csGRP78.