AHR-activated Stab1+Ly6G+ macrophages elicit resolution of pulmonary fibrosis-associated pathology 2328474

Abstract Introduction In response to various inflammatory stimuli, bone marrow-derived macrophages replace tissue-resident macrophages and mediate tissue inflammation to reestablish tissues homeosis. When inflammation becomes persistent and uncontrolled, however, inflammatory macrophages differentiate into pro-fibrotic macrophages, causing dysregulated fibrotic reactions. It remains largely unknown if macrophages with fibrosis-resolving capacity emerge during fibrogenesis. Methods Using the hyperlipidemia drug fenofibrate that was identified here as a novel ligand for the aryl hydrocarbon receptor (AHR), we showed that its activation promoted Ly6G+ lung macrophage differentiation and activation, resulting in resolution of pulmonary fibrosis. Results Fenofibrate-activated AHR in macrophages created a complex with c-MAF and induced expression of unique sets of genes that were critical in multiple resolving processes of lung homeostasis. Ly6G+ macrophages produced three categories of effector molecules produced by Ly6G+ macrophages to divide labor for resolution of pulmonary fibrosis-associated pathology: 1) GM-CSF drove monocyte-derived macrophage differentiation toward alveolar macrophages and Ly6G+ macrophages themselves; 2) spermidine promoted alveolar regeneration; and 3) metalloproteases (in particular, MMP14) recovered collagen deposition. Lungs of pulmonary fibrosis patients contained reparative, anti-fibrotic Stabilin-1 + (Stab1+) macrophages corresponding to mouse Ly6G+ macrophages and these cells could be differentiated from inflammatory monocytes after AHR stimulation with fenofibrate. Conclusion Thus, our study suggests that AHR-mediated activation of reparative, anti-fibrotic lung macrophages may provide a therapeutic strategy for the treatment of pulmonary fibrosis. Funding Source BK-21 FOUR program through National Research Foundation of Korea (NRF) under Ministry of Education, Republic of Korea Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)