Mechanosignaling promotes macrophage apoptosis resistance in pulmonary fibrosis via metabolic reprogramming

The mechanisms underlying disease progression in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases remain unclear. Increased extracellular matrix stiffness is a hallmark of fibrotic lung diseases, while monocyte-derived macrophages promote fibrosis progression. However, there is limited understanding if mechanical properties of the fibrotic microenvironment influence macrophage phenotypes and fibrogenesis. Profibrotic macrophages are resistant to apoptosis, which is modulated by enhanced mitochondrial bioenergetics. The objective of this study is to determine how lung tissue stiffness impacts macrophage phenotypes and fibrotic progression. We demonstrate that mechanoactivated macrophages exhibit apoptosis-resistance, increased expression of the antiapoptotic protein Bcl-xL, and elevated mitochondrial oxidative phosphorylation. Critically, the metabolic reprogramming observed in mechanoactivated macrophages is dependent on increased glutaminolysis. Inhibition of glutaminolysis attenuated apoptosis resistance in mechanoactivated macrophages. Moreover, inhibition of Bcl-xL in vivo protected mice against experimental pulmonary fibrosis. Lastly, mechanoactivated macrophages produce more profibrotic cytokines and promote extracellular matrix production in precision-cut lung slices. We describe a mechanism by which extracellular matrix stiffness mediates macrophage apoptosis resistance and metabolic reprogramming. Our results identify mechanoactivated apoptosis-resistant macrophages as pro-fibrotic mediators, suggesting a novel therapeutic target in IPF and related fibrotic disorders.