Neutrophil S100A9 supports M2 macrophage niche formation in granulomas
Tatsuaki Mizutani,
Toshiaki Ano,
Yuya Yoshioka,
Satoshi Mizuta,
Keiko Takemoto,
Yuki Ouchi,
Daisuke Morita,
Satsuki Kitano,
Hitoshi Miyachi,
Tatsuaki Tsuruyama,
Nagatoshi Fujiwara,
Masahiko Sugita
Affiliations
Tatsuaki Mizutani
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Corresponding author
Toshiaki Ano
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Yuya Yoshioka
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Satoshi Mizuta
Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Keiko Takemoto
Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
Yuki Ouchi
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Daisuke Morita
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Satsuki Kitano
Reproductive Engineering Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
Hitoshi Miyachi
Reproductive Engineering Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
Tatsuaki Tsuruyama
Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Nagatoshi Fujiwara
Department of Food and Nutrition, Tezukayama University, Nara, Japan
Masahiko Sugita
Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Summary: Mycobacterium infection gives rise to granulomas predominantly composed of inflammatory M1-like macrophages, with bacteria-permissive M2 macrophages also detected in deep granulomas. Our histological analysis of Mycobacterium bovis bacillus Calmette-Guerin-elicited granulomas in guinea pigs revealed that S100A9-expressing neutrophils bordered a unique M2 niche within the inner circle of concentrically multilayered granulomas. We evaluated the effect of S100A9 on macrophage M2 polarization based on guinea pig studies. S100A9-deficient mouse neutrophils abrogated M2 polarization, which was critically dependent on COX-2 signaling in neutrophils. Mechanistic evidence suggested that nuclear S100A9 interacts with C/EBPβ, which cooperatively activates the Cox-2 promoter and amplifies prostaglandin E2 production, followed by M2 polarization in proximal macrophages. Because the M2 populations in guinea pig granulomas were abolished via treatment with celecoxib, a selective COX-2 inhibitor, we propose the S100A9/Cox-2 axis as a major pathway driving M2 niche formation in granulomas.
