Parasite-Induced IFN-γ Regulates Host Defense via CD115 and mTOR-Dependent Mechanism of Tissue-Resident Macrophage Death

Abstract

ABSTRACTHost resistance to a common protozoan parasiteToxoplasma gondiirelies on a coordinated immune response involving multiple cell types, including macrophages. Embryonically seeded tissue-resident macrophages (TRMs) play a critical role in maintaining tissue homeostasis but their role in parasite clearance is poorly understood. In this study, we uncovered a crucial aspect of host defense againstT. gondiimediated by TRMs. Through the use of neutralizing antibodies and conditional IFN-γ receptor-deficient mice, we demonstrated that IFN-γ directly mediated the elimination of TRMs. Mechanistically, IFN-γ stimulation rendered macrophages unresponsive to macrophage colony-stimulating factor (M-CSF) and inactivated mTOR signaling by causing the shedding of CD115 (CSFR1), the receptor for M-CSF. Further experiments revealed the essential role of macrophage IFN-γ responsiveness in host resistance toT. gondii.The elimination of peritoneal TRMs emerged as a host defense mechanism aimed at limiting the parasite’s reservoir. The identified mechanism, involving IFN-γ-induced CD115 and mTOR-dependent cell death, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens.