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The chemokine CCL7 (MCP3) is known to promote the recruitment of many innate immune cell types including monocytes and neutrophils to sites of bacterial and viral infection and eosinophils and basophils to sites of allergic inflammation. CCL7 upregulation has been associated with many inflammatory settings including infection, cardiovascular disease, and the tumor microenvironment. CCL7's pleotropic effects are due in part to its ability to bind numerous chemokine receptors, namely CCR1, CCR2, CCR3, CCR5, and CCR10. CCL7-blockade or CCL7-deficiency is often marked by decreased inflammation and poor pathogen control. In the context of  Leishmania major  infection, CCL7 is specifically upregulated in the skin one-2 weeks after infection but its role in  L. major  control is unclear. To determine CCL7's impact on the response to  L. major  we infected WT and CCL7 −/−  C57BL/6 mice.  L. major  infection of CCL7-deficient mice led to an unexpected  increase  in inflammation in the infected skin 2 weeks post-infection. A broad increase in immune cell subsets was observed but was dominated by enhanced neutrophilic infiltration. Increased neutrophil recruitment was associated with an enhanced IL-17 gene profile in the infected skin. CCL7 was shown to directly antagonize neutrophil migration  in vitro  and CCL7 add-back  in vivo  specifically reduced neutrophil influx into the infected skin revealing an unexpected role for CCL7 in limiting neutrophil recruitment during  L. major  infection. Enhanced neutrophilic infiltration in CCL7-deficient mice changed the balance of  L. major  infected host cells with an increase in the ratio of infected neutrophils over monocytes/macrophages. To determine the consequence of CCL7 deficiency on  L. major  control we analyzed parasite load cutaneously at the site of infection and viscerally in the draining LN and spleen. The CCL7 −/−  mice supported robust cutaneous parasite control similar to their WT C57BL/6 counterparts. In contrast, CCL7-deficiency led to greater parasite dissemination and poor parasite control in the spleen. Our studies reveal a novel role for CCL7 in negatively regulating cutaneous inflammation, specifically neutrophils, early during  L. major  infection. We propose that CCL7-mediated dampening of the early immune response in the skin may limit the ability of the parasite to disseminate without compromising cutaneous control.

CCL7 Is a Negative Regulator of Cutaneous Inflammation Following Leishmania major Infection