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

• Published in: Cell research Vol. 21; no. 7; pp. 1068 - 1079
• Main Authors: Pietras, Eric M, Miller, Lloyd S, Johnson, Carl T, O'Connell, Ryan M, Dempsey, Paul W, Cheng, Genhong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2011; Nature Publishing Group
• Subjects: 631/250/2504/342; 631/80/86; 692/699/255/1318; Allografts; Animals; Antimicrobial agents; Bacteria; Biomedical and Life Sciences; Bone marrow; CC chemokine receptors; CCR2 protein; Cell activation; Cell Biology; Chemokine CCL2 - immunology; Chemokines; Circuits; Francisella tularensis; Francisella tularensis - physiology; gamma -Interferon; Gene Deletion; Gene Expression; Host-Pathogen Interactions; Immune response; Immunity, Innate; Infection; Interferon gamma Receptor; Life Sciences; Macrophages; Mice - immunology; Mice - microbiology; Monocyte chemoattractant protein 1; Monocytes; Monocytes - cytology; Monocytes - immunology; Monocytes - microbiology; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Original; original-article; Receptors, CCR2 - genetics; Receptors, CCR2 - immunology; Receptors, Interferon - genetics; Receptors, Interferon - immunology; Signal Transduction; Spleen; Spleen - cytology; Tularemia - immunology; monocyte; chemokine; infection; bacteria; interferon
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2011.59

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-γ (IFNγ)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 IFNγ, and IFNγR-deficient mice exhibited defective production of MCP-1, the ligand for CCR2. Transplantation of IFNγR-deficient bone marrow (BM) into wild-type mice further suggested that mobilization of monocytes in response to F. tularensis challenge required IFNγR expression on BM-derived cells. These studies define a critical host defense circuit wherein MyD88-dependent IFNγ production signals via IFNγR 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.