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

Significance Inflammation regulation and homeostasis maintenance is of paramount importance for lung health. Using both genetic and pathological mouse models, this work reveals that the secreted proapoptotic isthmin 1 (ISM1) protects lung homeostasis by controlling alveolar macrophage (AM) population and functional phenotype via cell-surface GRP78 (csGRP78)-mediated apoptosis. In both mouse and human, AMs express varied amount of csGRP78, enabling ISM1 to selectively remove the proinflammatory csGRP78 high AMs via apoptosis. In cigarette smoke–induced chronic obstructive pulmonary disease (COPD) mice, pulmonary delivery of recombinant ISM1 (rISM1) suppressed lung inflammation, blocked emphysema development, and preserved lung function. This work reveals molecular insights for lung homeostasis regulation and offers a rationale to target csGRP78 with pulmonary-delivered rISM1 as a potential therapeutic strategy for COPD.