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

Shuhua Luo1, Chaoxiong Liao1, Lina Zhang1

  • 1Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China.

Cell Reports
|March 15, 2023
PubMed

Insights

Methyltransferase-like protein 3 (METTL3) regulates neutrophil activation by modifying Toll-like receptor 4 (TLR4) mRNA. This m6A modification increases TLR4 levels, enhancing inflammatory responses in endotoxemia.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) is a prevalent mRNA modification regulating gene expression.
  • Neutrophil activation plays a key role in inflammatory processes like endotoxemia.

Purpose of the Study:

  • To investigate the role of methyltransferase-like protein 3 (METTL3) in neutrophil activation during endotoxemia.
  • To elucidate the mechanism by which METTL3 influences Toll-like receptor 4 (TLR4) signaling.

Main Methods:

  • Studied METTL3's role in neutrophil release and activation.
  • Analyzed m6A modification of Toll-like receptor 4 (TLR4) mRNA.
  • Investigated downstream signaling pathways including TLR4/Myd88/NF-κB.

Main Results:

  • METTL3 controls neutrophil release via CXCR2 in a TLR4-dependent manner.
  • m6A modification of TLR4 mRNA increases its translation and stability, elevating protein levels.
  • METTL3 deletion reduces TLR4 expression and subsequent cytokine secretion in LPS-stimulated neutrophils.

Conclusions:

  • METTL3-mediated m6A modification of TLR4 is critical for neutrophil activation in endotoxemia.
  • METTL3 acts as a key regulator of the TLR4 signaling pathway, impacting inflammatory responses.
Keywords:
CP: ImmunologyMETTL3TLR4inflammationm6Aneutrophil

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