Parasite-induced IFN-γ regulates host defense via CD115 and mTOR-dependent mechanism of tissue-resident macrophage death.

Autor: Martin, Andrew T., Giri, Shilpi, Safronova, Alexandra, Eliseeva, Sophia I., Kwok, Samantha F., Yarovinsky, Felix
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Zdroj: PLoS Pathogens; 2/20/2024, Vol. 20 Issue 2, p1-22, 22p
Abstrakt: Host resistance to a common protozoan parasite Toxoplasma gondii relies 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 against T. gondii mediated 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 in vivo 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 to T. gondii. The elimination of peritoneal TRMs emerged as an additional host defense mechanism aimed at limiting the parasite's reservoir. The identified mechanism, involving IFN-γ-induced suppression of CD115-dependent mTOR signaling in macrophages, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens. Author summary: This study revealed a vital aspect of host defense mediated by the rapid loss of tissue-resident macrophages (TRMs) during the acute phase of infection with the common protozoan parasite Toxoplasma gondii. The researchers found that IFN-γ, a crucial cytokine for host resistance against T. gondii and other intracellular pathogens, was responsible for the rapid elimination of TRMs. Through experiments with mice lacking receptors for this cytokine, the team demonstrated that IFN-γ causes the death of TRMs. Mechanistically, IFN-γ renders macrophages unresponsive to the macrophage growth factor M-CSF by inducing the shedding of its receptor, known as CD115, and subsequently inhibiting mTOR activation. The loss of responsiveness to M-CSF resulted in the selective death of TRMs and their replacement by proinflammatory monocyte-derived macrophages that, at least at the site of infection, did not depend on M-CSF. The study revealed the importance of TRM loss in response to IFN-γ as a host defense mechanism, effectively limiting the niche for parasite replication. This discovery sheds light on how IFN-γ regulated macrophages during microbial infections. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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