| First Author | Wang X | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 1185 |
| PubMed ID | 36864027 | Mgi Jnum | J:360026 |
| Mgi Id | MGI:7441428 | Doi | 10.1038/s41467-023-36865-7 |
| Citation | Wang X, et al. (2023) N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice. Nat Commun 14(1):1185 |
| abstractText | 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 m(6)A methylation of Spi2a in macrophages. m(6)A-methylated Spi2a directly binds to IKKbeta to impair IKK complex formation and inactivate the NF-kappaB pathway. The loss of m(6)A 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-1beta and IFNgamma. Altogether, these findings suggest that m(6)A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis. |
