Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by irreversible remodeling of the lungs. Fibroblasts and macrophages have direct communication in the fibrotic microenvironment, and monocyte-derived macrophages (MDMs) localized within the fibrotic niche mediate fibroblast activation. Here, we determined if Hedgehog (Hh) signaling is activated in IPF lungs to regulate MDM metabolic reprogramming through fibroblast-macrophage interaction. Methods Levels of active Shh in BAL fluid and Hh activation in lung macrophages were determined in normal and IPF subjects and mice exposed to saline or bleomycin. BAL cells and lung tissue were subjected to FACS analysis to distinguish macrophage and fibroblast subsets. Cell-specific inducible knockout mouse models were utilized to investigate fibroblast-derived Shh and Hh signaling in MDMs. Results MDMs from IPF subjects had significantly greater maximal oxidative phosphorylation than the tissue resident alveolar macrophages. The conditional deletion of Shh in fibroblasts protected mice from established fibrosis and abrogated macrophage metabolic reprogramming to oxidative phosphorylation. Gli1 binding to the Cpt1a promotor was required for oxidative phosphorylation in macrophages. The conditional deletion of Smo in MDMs reversed established fibrosis, and constitutive activation of Smo in MDMs mediated fibrosis in the absence of lung injury. Moreover, a Smo inhibitor, ENV-101, reversed established fibrosis in a dose-dependent manner. Conclusions These observations indicated that fibroblast-derived Shh regulates metabolic reprogramming in macrophages via Hh signaling to mediate progressive fibrotic remodeling of the lung. This abstract is funded by: R01HL175661, R01HL176770
Larson-Casey et al. (Fri,) studied this question.