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

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.

SUBMITTER: Wang X

PROVIDER: S-EPMC9979126 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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N<sup>6</sup>-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice.

Wang Xiangyu X Ding Yan Y Li Ran R Zhang Rujun R Ge Xuejun X Gao Ruifang R Wang Miao M Huang Yubing Y Zhang Fang F Zhao Bin B Liao Wang W Du Jie J

Nature communications 20230302 1

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 acetyltransfer ...[more]

PMID: 36864027

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Project description:Background and aimsThe triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.MethodsThe relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9-/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.ResultsIn sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9-/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9-/- mice, confirming target specificity.ConclusionElevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.

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

Publications

N<sup>6</sup>-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice.

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Dataset Information

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

Publications

N<sup>6</sup>-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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