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Stat3 in Resident Macrophages as a Repressor Protein of Inflammatory Response¹

Akihiro Matsukawa^2,*, Shinji Kudo^*, Takako Maeda^*, Kousuke Numata^*, Hiroyuki Watanabe^*, Kiyoshi Takeda, Shizuo Akira and Takaaki Ito^*

^* Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, School of Medicine, Kumamoto University, Kumamoto, Japan; Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3^flox/– mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3^flox/– mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3^flox/– mice into the control littermates resulted in increases in the peritoneal level of TNF-, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3^flox/– macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.

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