A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1β production in tissue-resident macrophages
Izumi Sasaki,
Yuri Fukuda-Ohta,
Chihiro Nakai,
Naoko Wakaki-Nishiyama,
Chizuyo Okamoto,
Daisuke Okuzaki,
Shuhei Morita,
Shiori Kaji,
Yuki Furuta,
Hiroaki Hemmi,
Takashi Kato,
Asumi Yamamoto,
Emi Tosuji,
Shin-Ichiroh Saitoh,
Takashi Tanaka,
Katsuaki Hoshino,
Shinji Fukuda,
Kensuke Miyake,
Etsushi Kuroda,
Ken J. Ishii,
Takao Iwawaki,
Koichi Furukawa,
Tsuneyasu Kaisho
Affiliations
Izumi Sasaki
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Corresponding author
Yuri Fukuda-Ohta
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan
Chihiro Nakai
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Naoko Wakaki-Nishiyama
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Chizuyo Okamoto
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Daisuke Okuzaki
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
Shuhei Morita
First Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Shiori Kaji
Second Department of Internal Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Yuki Furuta
Department of Thoracic and Cardiovascular Surgery, Wakayama Medical University, Wakayama 641-8509, Japan
Hiroaki Hemmi
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime 794-8555, Japan
Takashi Kato
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Asumi Yamamoto
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Emi Tosuji
Department of Dermatology, Wakayama Medical University, Wakayama 641-8509, Japan
Shin-Ichiroh Saitoh
Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Takashi Tanaka
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Yokohama, Kanagawa 230-0045, Japan
Katsuaki Hoshino
Department of Immunology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
Shinji Fukuda
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan; Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Kanagawa 210-0821, Japan; Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Kensuke Miyake
Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Etsushi Kuroda
Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan
Ken J. Ishii
Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Takao Iwawaki
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
Koichi Furukawa
Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Kasugai, Aichi 487-8501, Japan
Tsuneyasu Kaisho
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Corresponding author
Summary: Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α is required for CT- or CTB-induced IL-1β production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.
