METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112259
• Main Authors: Luo, Shuhua, Liao, Chaoxiong, Zhang, Lina, Ling, Chunxiu, Zhang, Xuedi, Xie, Pengyun, Su, Guomei, Chen, Zhanghui, Zhang, Liangqing, Lai, Tianwen, Tang, Jing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: Endotoxemia - genetics; Humans; inflammation; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; m6A; Methylation; Methyltransferases - genetics; Methyltransferases - metabolism; METTL3; neutrophil; Neutrophil Activation; RNA, Messenger - genetics; RNA, Messenger - metabolism; TLR4; Toll-Like Receptor 4 - metabolism; CP: Immunology; m6A; inflammation; neutrophil; TLR4; METTL3
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112259

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 neutrophils upon LPS stimulation through TLR4/Myd88/nuclear factor κB (NF-κB) signaling. Collectively, these data demonstrate that METTL3 modulation of TLR4 expression is a critical determinant of neutrophil activation in endotoxemia. [Display omitted] •METTL3 affects BM neutrophil release and retention in endotoxemia•Deletion of METTL3 impairs neutrophil activation by inhibiting TLR4 signaling•METTL3 regulates neutrophil mobility through TLR4 mediated expression of CXCR2•METTL3 initiates m6A modifications on TLR4 mRNA to promote its protein expression Luo et al. show that METTL3-mediated m6A modification controls neutrophil activation by regulating TLR4/Myd88/NF-κB signaling and modulating the expression of CXCR2 in a TLR4-dependent manner. TLR4 mRNA of neutrophil is marked by m6A, exhibiting increased translation and slowed degradation simultaneously, leading to elevated protein level.