Abstract
Abstract Host resistance to intracellular pathogens is dependent on the pleiotropic cytokine interferon gamma (IFN-γ) which activates myeloid cells, such as macrophages, and results in pathogen clearance. Macrophages safeguard most regions of the body participating in tissue homeostasis, disease surveillance, pathogen elimination, and resolution of inflammation. The peritoneal cavity is patrolled by two unique subsets of resident macrophages: monocyte-derived small peritoneal macrophages (SPMs) and embryonically-seeded large peritoneal macrophages (LPMs). To determine the roles of SPMs and LPMs during intracellular infections, we infected mice intraperitoneally with the intracellular parasite Toxoplasma gondii, a robust driver of IFN-γ-mediated type 1 immune responses. We observed that T. gondii triggers a distinctive response in LPMs and SPMs responding to parasitic infection. Through the use of neutralizing antibodies, recombinant IFN-γ, and mice conditionally lacking expression of the IFN-γ receptor in macrophages, we have shown that the direct effects of IFN-γ are both required and sufficient for selective reprogramming of peritoneal macrophage subsets in response to T. gondii infection. Molecular mechanisms underlying the macrophage subset-specific effects of IFN-γ were further dissected in vivo and in vitro through imaging and omics approaches. Our results revealed the peritoneal macrophage subset-specific responses to IFN-γ that are essential for host resistance to T. gondii. Supported by the URMC T32 Immunology Training Grant AI00728, NIH R01 GR501266, and the Burroughs Wellcome Fund.
Published Version
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