Melatonin suppresses the antiviral immune response to EMCV infection through intracellular ATP deprivation caused by mitochondrial fragmentation
Mariko Kikuchi,
Miki Kadena,
Haruka Fukamachi,
Takashi Takaki,
Shohei Matsui,
Sumire Hoashi-Takiguchi,
Hirobumi Morisaki,
Nataša Trtić,
Mina Mori,
Mie Kurosawa,
Momoe Itsumi,
Takahiro Funatsu,
Atsuo Sakurai,
Seikou Shintani,
Hiroki Kato,
Takashi Fujita,
Yasubumi Maruoka,
Hirotaka Kuwata
Affiliations
Mariko Kikuchi
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan; Department of Special Needs Dentistry, Division of Community-Based Comprehensive Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Miki Kadena
Department of Special Needs Dentistry, Division of Dentistry for Persons with Disabilities, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Haruka Fukamachi
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Takashi Takaki
Division of Electron Microscopy, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Shohei Matsui
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan; Department of Special Needs Dentistry, Division of Community-Based Comprehensive Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Sumire Hoashi-Takiguchi
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Hirobumi Morisaki
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Nataša Trtić
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan; Division of Periodontology and Oral Medicine, Division of Periodontology and Oral Medicine, Department of Dental Medicine, Faculty of Medicine, University of Banja Luka, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina
Mina Mori
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan; Department of Special Needs Dentistry, Division of Community-Based Comprehensive Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Mie Kurosawa
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Momoe Itsumi
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
Takahiro Funatsu
Department of Pediatric Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Atsuo Sakurai
Department of Pediatric Dentistry, Tokyo Dental College, Tokyo, 101-0061, Japan
Seikou Shintani
Department of Pediatric Dentistry, Tokyo Dental College, Tokyo, 101-0061, Japan
Hiroki Kato
Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, Bonn, 53105, Germany
Takashi Fujita
Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
Yasubumi Maruoka
Department of Special Needs Dentistry, Division of Community-Based Comprehensive Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan
Hirotaka Kuwata
Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan; Corresponding author.
Melatonin, a sleep hormone derived from the pineal gland, has an anti-inflammatory effect on the immune system in addition to modulating the brain nervous system. Previous studies have shown that melatonin suppresses signaling pathways downstream of multiple pattern recognition receptors on the innate immune cells during pathogen infection, but the specific mechanism of suppression has not been well understood. Using an encephalomyocarditis virus (EMCV) infection model in macrophages, we investigated the effects of melatonin on the antiviral response in innate immunity and found that melatonin attenuated the uptake of viral particles into macrophages. Furthermore, melatonin suppressed cytoskeletal regulation by decreasing ATP production by mitochondria. Finally, in an in vivo infection experiment, we also found that melatonin administration partially exacerbated the infection in the mouse brain. These results suggest that melatonin may have an inhibitory effect on excessive inflammation by suppressing cytoskeletal regulation in the innate immune system, but also suggest that suppression of inflammation may lead to insufficient protection against EMCV infection in vivo.
