N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice

Xiangyu Wang, Yan Ding, Ran Li, Rujun Zhang, Xuejun Ge, Ruifang Gao, Miao Wang, Yubing Huang, Fang Zhang, Bin Zhao, Wang Liao () and Jie Du ()
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Xiangyu Wang: Shanxi Medical University School and Hospital of Stomatology
Yan Ding: Hainan Provincial Hospital of Skin Disease
Ran Li: Shanxi Medical University School and Hospital of Stomatology
Rujun Zhang: Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University
Xuejun Ge: Shanxi Medical University School and Hospital of Stomatology
Ruifang Gao: Shanxi Medical University School and Hospital of Stomatology
Miao Wang: Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University
Yubing Huang: Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University
Fang Zhang: Shanxi Medical University School and Hospital of Stomatology
Bin Zhao: Shanxi Medical University School and Hospital of Stomatology
Wang Liao: Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University
Jie Du: Shanxi Medical University School and Hospital of Stomatology

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m6A methylation of Spi2a in macrophages. m6A-methylated Spi2a directly binds to IKKβ to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m6A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1β and IFNγ. Altogether, these findings suggest that m6A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis.

Date: 2023
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DOI: 10.1038/s41467-023-36865-7

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