O6-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK

Salisa Benjaskulluecha; Atsadang Boonmee; MdFazlul Haque; Benjawan Wongprom; Thitiporn Pattarakankul; Chitsuda Pongma; Kittitach Sri-Ngern-Ngam; Pornlapat Keawvilai; Thadaphong Sukdee; Benjawan Saechue; Patipark Kueanjinda; Tanapat Palaga

doi:10.1016/j.isci.2023.108733

O⁶-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK

iScience. 2023 Dec 14;27(1):108733. doi: 10.1016/j.isci.2023.108733. eCollection 2024 Jan 19.

Authors

Salisa Benjaskulluecha^{1

2

3}, Atsadang Boonmee^{2

3

4}, MdFazlul Haque^{2

3}, Benjawan Wongprom^{2

3}, Thitiporn Pattarakankul^{3

5}, Chitsuda Pongma^{3

6}, Kittitach Sri-Ngern-Ngam^{2

3}, Pornlapat Keawvilai^{3

6}, Thadaphong Sukdee^{1

2

3}, Benjawan Saechue^{2

3

7}, Patipark Kueanjinda^{1

2

8}, Tanapat Palaga^{1

2

3}

Affiliations

¹ Interdisciplinary Graduate Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
² Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok 10330, Thailand.
³ Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
⁴ Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
⁵ Center of Excellence in Advanced Materials and Biointerfaces, Chulalongkorn University, Bangkok 10330, Thailand.
⁶ Graduate Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
⁷ One Health Research Unit, Faculty of Veterinary Science, Mahasarakham University, Mahasarakham 44000, Thailand.
⁸ Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

Abstract

Trained immunity is the heightened state of innate immune memory that enhances immune response resulting in nonspecific protection. Epigenetic changes and metabolic reprogramming are critical steps that regulate trained immunity. In this study, we reported the involvement of O⁶-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme of lesion induced by alkylating agents, in regulation the trained immunity induced by β-glucan (BG). Pharmacological inhibition or silencing of MGMT expression altered LPS stimulated pro-inflammatory cytokine productions in BG-trained bone marrow derived macrophages (BMMs). Targeted deletion of Mgmt in BMMs resulted in reduction of the trained responses both in vitro and in vivo models. The transcriptomic analysis revealed that the dampening trained immunity in MGMT KO BMMs is partially mediated by ATM/FXR/AMPK axis affecting the MAPK/mTOR/HIF1α pathways and the reduction in glycolysis function. Taken together, a failure to resolve a DNA damage may have consequences for innate immune memory.

Keywords: Cell biology; Immunology; Molecular biology; Transcriptomics.