Volume 21, No 7, Jul 2011
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 21 Issue 7, July 2011: 1068-1079
ORIGINAL ARTICLES
A MyD88-dependent IFNγR-CCR2 signaling circuit is required for mobilization of monocytes and host defense against systemic bacterial challenge
Eric M Pietras1, Lloyd S Miller1,2, Carl T Johnson1, Ryan M O'Connell1, Paul W Dempsey1,5 and Genhong Cheng1,2,3,4
1Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
2Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
3Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA
4Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA
5Current address: Cynvenio Biosystems LLC, Westlake Village, CA 91361, USA
Correspondence: Genhong Cheng,(gcheng@mednet.ucla.edu)
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.
Cell Research (2011) 21:1068-1079. doi:10.1038/cr.2011.59; published online 5 April 2011
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