METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling
METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling
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DOI：
10.1016/j.celrep.2023.112259
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发表时间：
2023-03-14
期刊：
影响因子：
8.8
通讯作者：
Tang, Jing
中科院分区：
文献类型：
--
作者：
Luo, Shuhua;Liao, Chaoxiong;Tang, Jing
n6 -甲基腺苷（m6A）修饰是最常见的mRNA内部修饰，在多种生理过程中作为一种广泛的调控机制而出现。我们研究了甲基转移酶样蛋白3 （METTL3）在中性粒细胞活化中的作用。在脂多糖（LPS）诱导的内毒素血症中，METTL3以Toll样受体4 （TLR4）信号依赖的方式，通过CXC趋化因子受体2 （CXCR2）的表面表达，控制中性粒细胞从骨髓向循环的释放。我们发现，TLR4的mRNA被m6A修饰，同时表现出翻译增加和降解减慢，导致TLR4蛋白水平升高，最终促进中性粒细胞的TLR4信号激活。TLR4表达的减少通过TLR4/Myd88/ NF-KB信号通路降低mettl3缺失的新嗜细胞在LPS刺激下的细胞因子分泌。总的来说，这些数据表明，METTL3对TLR4表达的调节是内毒素血症中性粒细胞激活的关键决定因素。
N6-methyladenosine (m6A) modification accounts for the most prevalent mRNA internal modification and has emerged as a widespread regulatory mechanism in multiple physiological processes. We address a role of methyltransferase-like protein 3 (METTL3) in neutrophil activation. METTL3 controls neutrophil release from bone marrow to circulation through surface expression of CXC chemokine receptor 2 (CXCR2) in a Toll -like receptor 4 (TLR4) signaling-dependent manner in lipopolysaccharide (LPS)-induced endotoxemia. We show that the mRNA of TLR4 is modified by m6A, exhibiting increased translation and slowed degradation simultaneously, leading to elevated protein levels of TLR4, which eventually promotes the TLR4 signaling activation of neutrophil. The reduced expression of TLR4 lowers cytokine secretion in METTL3-deleted neu-trophils upon LPS stimulation through TLR4/Myd88/nuclear factor KB (NF-KB) signaling. Collectively, these data demonstrate that METTL3 modulation of TLR4 expression is a critical determinant of neutrophil activa-tion in endotoxemia.