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A1007 - The Differential Regulation of Monocyte Derived and Tissue Resident Alveolar Macrophages by mTORC2 Promotes Lung Fibrosis
Author Block: M. R. Horton, S. Collins, M. Oh, Y. Chan-Li, J. Powell; Johns Hopkins University Schoo of Medicine, Baltimore, MD, United States.
Rationale: The exact biologic programs that result in lung healing versus fibrosis are unknown. New studies point to monocyte-derived alveolar macrophages (MoAM) as playing a critical role in the pathogenesis of fibrosis. These bone marrow derived MoAM cells are distinct from self-renewing tissue resident alveolar macrophages (TRAM) derived from embryonic liver. Indeed, the TRAM are believed to maintain lung homeostasis and be first responders to injury. The role of TRAM in pulmonary fibrosis has yet to be determined. Recently, our lab has been able to demonstrate a critical role for mTOR in regulating macrophage activation, differentiation and function. We have defined a critical role for mTOR Complex II (mTORC2) in promoting M2 macrophage differentiation. Mice in which Rictor has been selectively deleted in macrophages fail to mount M2 responses in vivo and have impaired immunity to parasites. In addition, we have demonstrated a novel role for mTORC2 in regulating GATA6+ tissue resident peritoneal macrophages. We hypothesize that macrophage mTORC2 potentiates the development of lung inflammation and fibrosis via differential regulation of monocyte derived and tissue resident alveolar macrophages. Methods: Chronic pulmonary fibrosis is induced by intraperitoneal injections of bleomycin over 4 weeks in WT and mRictor-/- (LysM-cre macrophage deletion of mTORC2 activity). Mice are harvested on day 42, and the degree of fibrosis is assessed by histology, collagen, and pulmonary function testing. Lung inflammatory cells are analyzed by FACS analysis and inflammatory cytokines by ELISA and PCR. Results: On D42 after bleomycin injury, when compared to WT mice, mice deficient in macrophage mTORC2 have decreased mortality, collagen, histologic damage, lung fibrocytes and improved lung function (improved oxygen transfer and compliance) as well as decreased M2 macrophages, Th17 cells and IL-6. Furthermore, there is a decrease in the pro-fibrotic MoAM and an increase in the pro-healing TRAM in the mice deficient in macrophage mTORC2. Conclusions: Our results reveal a critical role for macrophage mTORC2 in promoting bleomycin induced lung fibrosis by regulating the differentiation and function alveolar macrophage subsets. Specifically, macrophage mTORC2 promotes MoAMs that express M2 cytokines that promote fibrosis but inhibits the generation of TRAMs that promote normal wound healing. Exploiting the unique roles of mTORC2 in macrophage differentiation will provide important insight into the mechanisms that contribute to the dysregulated inflammation that promotes lung fibrosis as well as identifying potential novel therapeutic targets.