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* Infectious Diseases Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065; and
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158
Chemokine receptor-mediated recruitment of inflammatory cells is essential for innate immune defense against microbial infection. Recruitment of Ly6Chigh inflammatory monocytes from bone marrow to sites of microbial infection is dependent on CCR2, a chemokine receptor that responds to MCP-1 and MCP-3. Although CCR2–/– mice are markedly more susceptible to Listeria monocytogenes infection than are wild-type mice, MCP-1–/– mice have an intermediate phenotype, suggesting that other CCR2 ligands contribute to antimicrobial defense. Herein, we show that L. monocytogenes infection rapidly induces MCP-3 in tissue culture macrophages and in serum, spleen, liver, and kidney following in vivo infection. Only cytosol invasive L. monocytogenes induce MCP-3, suggesting that cytosolic innate immune detection mechanisms trigger chemokine production. MCP-3–/– mice clear bacteria less effectively from the spleen than do wild-type mice, a defect that correlates with diminished inflammatory monocyte recruitment. MCP-3–/– mice have significantly fewer Ly6Chigh monocytes in the spleen and bloodstream, and increased monocyte numbers in bone marrow. MCP-3–/– mice, like MCP-1–/– mice, have fewer TNF- and inducible NO synthase-producing dendritic cells (Tip-DCs) in the spleen following L. monocytogenes infection. Our data demonstrate that MCP-3 and MCP-1 provide parallel contributions to CCR2-mediated inflammatory monocyte recruitment and that both chemokines are required for optimal innate immune defense against L. monocytogenes infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health grants (R37AI03903 to E.G.P. and R01 HL52773 and R01 HL63894 to I.F.C.).
2 Address correspondence and reprint requests to Dr. Eric G. Pamer, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 9, New York, NY 10021. E-mail address: pamere{at}mskcc.org
3 Abbreviations used in this paper: DC, dendritic cell; GAG, glycosaminoglycan; HKL, heat-killed Listeria monocytogenes; iNOS, inducible NO synthase; LLO, listeriolysin O; Tip-DC, TNF- and iNOS-producing DC; WT, wild type.
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