Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Chaoxiong Liao
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Lina Zhang
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Chunxiu Ling
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Xuedi Zhang
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Pengyun Xie
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Guomei Su
Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Zhanghui Chen
Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang 524000, Guangdong, China
Liangqing Zhang
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Corresponding author
Tianwen Lai
Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Corresponding author
Jing Tang
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China; Corresponding author
Summary: 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.
