Neutrophil S100A9 supports M2 macrophage niche formation in granulomas

  • iScience. 2023 Jan 31;26(3):106081. doi: 10.1016/j.isci.2023.106081.
Tatsuaki Mizutani  1  2 ,  Toshiaki Ano  1  2 ,  Yuya Yoshioka  1  2 ,  Satoshi Mizuta  3 ,  Keiko Takemoto  4 ,  Yuki Ouchi  1  2 ,  Daisuke Morita  1  2 ,  Satsuki Kitano  5 ,  Hitoshi Miyachi  5 ,  Tatsuaki Tsuruyama  6 ,  Nagatoshi Fujiwara  7 ,  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.
PMID: 36843852 DOI: 10.1016/j.isci.2023.106081
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.
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