F-030. Increased IL-4 Production By Macrophages in CCR2-/- Mice Results in the Inability to Resolve Histoplasma capsulatum Infection

F-030. Increased IL-4 Production By Macrophages in CCR2^-/- Mice Results in the Inability to Resolve Histoplasma capsulatum Infection

W. A. Szymczak, G. S. Deepe, Jr.;
Univ. of Cincinnati Coll. of Med., Cincinnati, OH.

Signaling through the chemokine receptor CCR2 is necessary for mediating inflammatory cell recruitment to sites of infection as well as maintaining a T_H1 response in some infection models. We sought to determine if chemokine signaling also contributes to inflammation and immunity to infection by the dimorphic fungus Histoplasma capsulatum. Mice lacking the chemokine receptor CCR2 were infected with a sublethal dose of H. capsulatum to determine if knockout mice could survive infection. At day 7 post infection, CCR2^-/- mice exhibited increased fungal burden in the lungs and all CCR2^-/- mice succumbed by day 26. In addition to decreased inflammatory cell recruitment of all leukocytes and decreased relative percentages of monocytes, macrophages, and dendritic cells within the lungs, CCR2^-/- mice exhibited increased IL-4 levels over the course of infection in comparison to controls. Neutralization of IL-4 in CCR2^-/- mice decreased fungal burden to control levels and prevented mortality. Neutralization of IL-4 did not restore leukocyte recruitment suggesting that the increased IL-4 levels in CCR2^-/- mice do not effect inflammation but do dampen immunity. Utilizing an IL-4 secretion assay, we determined the source of IL-4 in CCR2^-/- mice to be predominantly of macrophage origin. Of the IL-4 secreting leukocytes, ~80% were Mac3+, CD11c+ macrophages whereas only ~10% were CD3+ T cells. Bone marrow-derived macrophages were infected in vitro to determine if IL-4 is induced in response to H. capsulatum infection. Infection of bone marrow-derived macrophages resulted in increased IL-4 production in a H. capsulatum yeast-dependent manner. These data suggest that an increased percentage of infected macrophages, more highly infected macrophages, and/or an amplified inability of CCR2^-/- macrophages to control yeast replication results in increased IL-4 production leading to the inability to resolve infection.