2. Academic Validation
  3. METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling

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

  • Cell Rep. 2023 Mar 13;42(3):112259. doi: 10.1016/j.celrep.2023.112259.
Shuhua Luo 1,  Chaoxiong Liao 1,  Lina Zhang 1,  Chunxiu Ling 1,  Xuedi Zhang 1,  Pengyun Xie 2,  Guomei Su 3,  Zhanghui Chen 4,  Liangqing Zhang 5,  Tianwen Lai 6,  Jing Tang 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
  • 2 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
  • 3 Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
  • 4 Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
  • 5 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China. Electronic address: zhanglq1970@163.com.
  • 6 Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China. Electronic address: laitianwen2011@163.com.
  • 7 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China. Electronic address: tanglitangjing@126.com.
PMID: 36920907 DOI: 10.1016/j.celrep.2023.112259
Abstract

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.

Keywords

CP: Immunology; METTL3; TLR4; inflammation; m6A; neutrophil.

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