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

doi:10.1016/j.isci.2023.106081

Neutrophil S100A9 supports M2 macrophage niche formation in granulomas

iScience. 2023 Jan 31;26(3):106081. doi: 10.1016/j.isci.2023.106081. eCollection 2023 Mar 17.

Authors

Tatsuaki Mizutani^{1

2}, Toshiaki Ano^{1

2}, Yuya Yoshioka^{1

2}, Satoshi Mizuta³, Keiko Takemoto⁴, Yuki Ouchi^{1

2}, Daisuke Morita^{1

2}, Satsuki Kitano⁵, Hitoshi Miyachi⁵, Tatsuaki Tsuruyama⁶, Nagatoshi Fujiwara⁷, Masahiko Sugita^{1

2}

Affiliations

¹ Laboratory of Cell Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
² Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
³ Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
⁴ Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
⁵ Reproductive Engineering Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
⁶ Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁷ Department of Food and Nutrition, Tezukayama University, Nara, Japan.

Abstract

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.

Keywords: Cancer; Components of the immune system; Immunology; Molecular biology.