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Abstract
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme. The roles of this enzyme in immune cells remain unclear. In this study, we explored the roles of MGMT in bone marrow-derived murine macrophages (BMMs) via the use of MGMT knockout (KO) mice. Loss of MGMT altered the response to TLR3 agonists (poly (I:C)), such as dampening the production of TNFα and IL-6. Increased DNA double-strand breaks (DSBs) were observed in MGMT-KO macrophages but did not result in increased cell death. MGMT localized to both nuclei and mitochondria at increasing levels during poly (I:C) stimulation. MGMT deficiency increased the production of mitochondrial reactive oxygen species (mtROS), which was correlated with increased mitophagy. The underlying mechanism involves mediation through activation of the AMPKα pathway. Taken together, our findings reveal the roles of MGMT in macrophages in regulating the response to TLR3, which links DSBs to mtROS and mitophagy via the AMPKα pathway. These roles may have consequences for the inflammatory response and chronic inflammation.
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1 Chulalongkorn University, Department of Microbiology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); University of Rajshahi, Department of Zoology, Faculty of Biological Sciences, Rajshahi, Bangladesh (GRID:grid.412656.2) (ISNI:0000 0004 0451 7306)
2 Chulalongkorn University, Department of Microbiology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Chulalongkorn University, Center of Excellence in Immunology and Immune-Mediated Diseases, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
3 Chulalongkorn University, Department of Microbiology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Mahidol University, Department of Microbiology, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand (GRID:grid.10223.32) (ISNI:0000 0004 1937 0490)
4 Chulalongkorn University, Department of Microbiology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Chulalongkorn University, Center of Excellence in Advanced Materials and Biointerfaces, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
5 Chulalongkorn University, Program of Bachelor of Science in Applied Chemistry (BSAC), Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
6 Chulalongkorn University, Department of Microbiology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Chulalongkorn University, Graduate Program in Biotechnology, Faculty of Science, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
7 Mahasarakham University, One Health Research Unit, Faculty of Veterinary Science, Mahasarakham, Thailand (GRID:grid.411538.a) (ISNI:0000 0001 1887 7220)
8 Chulalongkorn University, Department of Microbiology, Faculty of Medicine, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
9 Oita University, Department of Infectious Disease Control, Faculty of Medicine, Research Center for GLOBAL and LOCAL Infectious Diseases, Oita, Japan (GRID:grid.412334.3) (ISNI:0000 0001 0665 3553)