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Updated: Aug 8, 2025
Author Spotlight: Advanced Integrated Model for Sepsis-Induced Myopathy and Single-Cell Metabolic Analysis
Published on: June 14, 2024
N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice
Xiangyu Wang1,2,3, Yan Ding4,5, Ran Li1,2,3
1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
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.
Insights
Sepsis inflammation is reduced by Spi2a methylation, which targets IKKβ to inactivate the NF-κB pathway. This epigenetic mechanism in macrophages offers a potential therapeutic target for sepsis treatment.
Area of Science:
- Immunology
- Molecular Biology
- Epigenetics
Background:
- Sepsis involves uncontrolled inflammation and organ dysfunction due to excessive pro-inflammatory cytokines.
- Current sepsis treatments face challenges in controlling this systemic inflammation.
Purpose of the Study:
- To investigate the role of Spi2a and its epigenetic regulation in macrophage-mediated sepsis inflammation.
- To elucidate the molecular mechanism by which Spi2a impacts inflammatory pathways in sepsis.
Main Methods:
- Lipopolysaccharide (LPS) stimulation of bone marrow-derived macrophages.
- Analysis of Spi2a expression, m6A methylation, and protein interactions (KAT2B, METTL14, IKKβ).
- Assessment of cytokine production and myocardial function in septic mouse models and human patient samples.
Main Results:
- LPS stimulation upregulates KAT2B, enhancing METTL14-mediated m6A methylation of Spi2a.
- m6A-methylated Spi2a inhibits IKKβ, impairing NF-κB pathway activation and reducing pro-inflammatory cytokine production.
- Loss of Spi2a methylation exacerbates sepsis phenotypes in mice, while Spi2a overexpression ameliorates them.
- Human SERPINA3 (Spi2a orthologue) mRNA levels inversely correlate with pro-inflammatory cytokines in septic patients.
Conclusions:
- m6A methylation of Spi2a acts as a negative regulator of macrophage activation during sepsis.
- Targeting Spi2a methylation presents a potential therapeutic strategy for sepsis management.
