Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s
Misato Irie,
Hiroki Kabata,
Kotaro Sasahara,
Momoko Kurihara,
Yoshitaka Shirasaki,
Takashi Kamatani,
Rie Baba,
Masako Matsusaka,
Satoshi Koga,
Katsunori Masaki,
Jun Miyata,
Yasutomo Araki,
Toru Kikawada,
Yasuaki Kabe,
Makoto Suematsu,
Mai Yamagishi,
Sotaro Uemura,
Kazuyo Moro,
Koichi Fukunaga
Affiliations
Misato Irie
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Hiroki Kabata
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Corresponding author
Kotaro Sasahara
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Momoko Kurihara
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Yoshitaka Shirasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
Takashi Kamatani
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; Department of AI Technology Development, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; Division of Precision Cancer Medicine, Tokyo Medical and Dental University Hospital, Tokyo 113-8519, Japan
Rie Baba
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Masako Matsusaka
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Satoshi Koga
Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Katsunori Masaki
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Jun Miyata
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Yasutomo Araki
Nose Clinic Tokyo, 1-3-1 Kyobashi Chuo-ku, Tokyo 104-0031, Japan
Toru Kikawada
Nose Clinic Tokyo, 1-3-1 Kyobashi Chuo-ku, Tokyo 104-0031, Japan
Yasuaki Kabe
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Makoto Suematsu
WPI Bio2Q Research Center, Keio University and Central Institute for Experimental Medicine, Kawasaki, Kanagawa 210-0821, Japan
Mai Yamagishi
Live Cell Diagnosis, Ltd., Asaka, Saitama 351-0022, Japan
Sotaro Uemura
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
Kazuyo Moro
Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Laboratory for Innate Immune Systems, Osaka University Immunology Frontier Research Center, Suita, Osaka 565-0871, Japan
Koichi Fukunaga
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Summary: Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s. The expression of ANXA1 decreases when ILC2s activate, but it increases autonomously as the activation subsides. Lentiviral vector-based gene transfer experiments show that ANXA1 suppresses the activation of human ILC2s. Mechanistically, ANXA1 regulates the expression of the metallothionein family genes, including MT2A, which modulate intracellular zinc homeostasis. Furthermore, increased intracellular zinc levels play an essential role in the activation of human ILC2s by promoting the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and GATA3 expression. Thus, the ANXA1/MT2A/zinc pathway is identified as a cell-intrinsic metalloregulatory mechanism for human ILC2s.
