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.

METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner

“…Uncontrolled inflammatory responses mediated by pulmonary macrophages are indeed crucial in the pathogenesis of ALI/ARDS [ 37 ]. In the present study, we found that METTL14 knockdown alleviated lung injury via inhibiting NLRP3 inflammasome activation in macrophages, consistent with the result in sepsis-associated myocardial dysfunction [ 38 ]. The NLRP3 inflammasome, which acts as the core of the inflammatory response, mediates caspase-1 activation and the secretion of proinflammatory cytokines, IL-1β/IL-18 [ 39 ].…”

Circulating Exosomes from Septic Mice Activate NF-κB/MIR17HG Pathway in Macrophages

“…In this study, abundant proteins were identified inside exosomes. Among these identified proteins, CD14 confers lipopolysaccharide (LPS)-responsiveness to cells and the subsequent toll-like receptor (TLR) signaling pathway [ 93 , 94 ]; SERPINA3F exerts an inhibitory function in cytokine production [ 95 ] and is upregulated in apoptosis [ 96 , 97 ]; H2AX is a variant of the histone protein H2A, which is a component of the nucleosome, the basic unit of chromatin. H2AX is essential for the response to DNA damage and the preservation of genome stability [ 98 , 99 ].…”

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

“…The effect was due to reduced degradation of Nod1 and receptor-interacting serine-threonine kinase 2 (Ripk2) mRNA. Similarly, loss of macrophage Mettl14 caused overactivation of the TLR4/nuclear factor κB (NF-κB) signaling pathway and sustained pro-inflammatory cytokine production via m6A modification of suppressor of cytokine signaling 1 (Socs1) and Serine protease inhibitor 2 A (Spi2a) [13,14].…”

“…Findings regarding the macrophage regulatory functions of m6A modifications have therapeutic implications for inflammatory disorders despite the fact that conflicting results have generated debate. Variations in experimental design, cell types, microbial species, and RNA targets may account for the heterogeneity of results and the complexity of underlying mechanisms may also be a factor [8][9][10][11][12][13][14]. Further investigation of the m6A modification in the monocyte/macrophage-mediated antimicrobial response and inflammation is merited.…”