A MyD88-dependent IFNγR-CCR2 signaling circuit is required for mobilization of monocytes and host defense against systemic bacterial challenge

Monocytes are mobilized to sites of infection via interaction between the chemokine MCP-1 and its receptor, CCR2, at which point they differentiate into macrophages that mediate potent antimicrobial effects. In this study, we investigated the mechanisms by which monocytes are mobilized in response to systemic challenge with the intracellular bacterium Francisella tularensis. We found that mice deficient in MyD88, interferon-gamma (IFN gamma)R or CCR2 all had defects in the expansion of splenic monocyte populations upon F. tularensis challenge, and in control of F. tularensis infection. Interestingly, MyD88-deficient mice were defective in production of IFN gamma, and IFN gamma R-deficient mice exhibited defective production of MCP-1, the ligand for CCR2. Transplantation of IFN gamma R-deficient bone marrow (BM) into wild-type mice further suggested that mobilization of monocytes in response to F. tularensis challenge required IFN gamma R expression on BM-derived cells. These studies define a critical host defense circuit wherein MyD88-dependent IFN gamma production signals via IFN gamma R expressed on BM-derived cells, resulting in MCP-1 production and activation of CCR2-dependent mobilization of monocytes in the innate immune response to systemic F. tularensis challenge.