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

doi:10.1016/j.heliyon.2022.e11149

Melatonin suppresses the antiviral immune response to EMCV infection through intracellular ATP deprivation caused by mitochondrial fragmentation

Heliyon. 2022 Oct 19;8(10):e11149. doi: 10.1016/j.heliyon.2022.e11149. eCollection 2022 Oct.

Authors

Mariko Kikuchi^{1

2}, Miki Kadena³, Haruka Fukamachi¹, Takashi Takaki⁴, Shohei Matsui^{1

2}, Sumire Hoashi-Takiguchi¹, Hirobumi Morisaki¹, Nataša Trtić^{1

5}, Mina Mori^{1

2}, Mie Kurosawa¹, Momoe Itsumi¹, Takahiro Funatsu⁶, Atsuo Sakurai⁷, Seikou Shintani⁷, Hiroki Kato⁸, Takashi Fujita⁹, Yasubumi Maruoka², Hirotaka Kuwata¹

Affiliations

¹ Department of Oral Microbiology and Immunology, Faculty of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan.
² 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.
³ 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.
⁴ Division of Electron Microscopy, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan.
⁵ 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.
⁶ Department of Pediatric Dentistry, Faculty of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo, 145-8515, Japan.
⁷ Department of Pediatric Dentistry, Tokyo Dental College, Tokyo, 101-0061, Japan.
⁸ Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, Bonn, 53105, Germany.
⁹ Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.

Abstract

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.

Keywords: Antiviral immunity; Cytokines; Inflammation; Innate immunity; Melatonin; Mitochondria; Neuro-immunology.