mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages
Min-Hee Oh,
Samuel L. Collins,
Im-Hong Sun,
Ada J. Tam,
Chirag H. Patel,
Matthew L. Arwood,
Yee Chan-Li,
Jonathan D. Powell,
Maureen R. Horton
Affiliations
Min-Hee Oh
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Samuel L. Collins
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Im-Hong Sun
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Ada J. Tam
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Chirag H. Patel
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Matthew L. Arwood
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Yee Chan-Li
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Jonathan D. Powell
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Maureen R. Horton
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well as in promoting inflammation and immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from the microenvironment that, in turn, regulate unique differentiation programs. Recently, a role for GATA6 has emerged in the differentiation programming of resident peritoneal macrophages. We identify a critical role for mTOR in integrating cues from the tissue microenvironment in regulating differentiation and metabolic reprogramming. Specifically, inhibition of mTORC2 leads to enhanced GATA6 expression in a FOXO1 dependent fashion. Functionally, inhibition of mTORC2 promotes peritoneal resident macrophage generation in the resolution phase during zymosan-induced peritonitis. Also, mTORC2-deficient peritoneal resident macrophages displayed increased functionality and metabolic reprogramming. Notably, mTORC2 activation distinguishes tissue-resident macrophage proliferation and differentiation from that of M2 macrophages. Overall, our data implicate a selective role for mTORC2 in the differentiation of tissue-resident macrophages.
