PFKFB3 promotes sepsis-induced acute lung injury by enhancing NET formation by CXCR4hi neutrophils

Dadong Liu; Min Xiao; Jing Zhou; Peng Wang; Jingwen Peng; Wenjian Mao; Yuepeng Hu; Yuxiu Liu; Jiangtao Yin; Lu Ke; Weiqin Li

doi:10.1016/j.intimp.2023.110737

PFKFB3 promotes sepsis-induced acute lung injury by enhancing NET formation by CXCR4^hi neutrophils

Int Immunopharmacol. 2023 Oct:123:110737. doi: 10.1016/j.intimp.2023.110737. Epub 2023 Aug 3.

Authors

Dadong Liu¹, Min Xiao¹, Jing Zhou¹, Peng Wang¹, Jingwen Peng², Wenjian Mao², Yuepeng Hu², Yuxiu Liu³, Jiangtao Yin⁴, Lu Ke⁵, Weiqin Li⁶

Affiliations

¹ Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, Jiangsu, China.
² Center of Severe Acute Pancreatitis (CSAP), Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
³ Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
⁴ Department of Critical Care Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China; Digestive Disease Institute, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China. Electronic address: doctoryjt2438@163.com.
⁵ Center of Severe Acute Pancreatitis (CSAP), Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China. Electronic address: ctgkelu@nju.edu.cn.
⁶ Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: liweiqindr@nju.edu.cn.

PMID: 37543012
DOI: 10.1016/j.intimp.2023.110737

Abstract

CXCR4^hi neutrophils, which are a subset of neutrophils with high CXCR4 expression, are important contributors to sepsis-induced acute lung injury (ALI). PFKFB3, a key glycolysis gene, plays an essential role in neutrophil inflammatory activation. However, the specific involvement of PFKFB3 in sepsis-induced ALI remains unclear. Here, we observed that PFKFB3 was upregulated in CXCR4^hi neutrophils and facilitated sepsis-induced ALI. Mechanistically, we observed that PFKFB3 promoted sepsis-induced ALI by enhancing neutrophil extracellular trap (NET) formation by CXCR4^hi neutrophils. Further study indicated that PFKFB3 promoted NET formation by upregulating glycolytic metabolism in CXCR4^hi neutrophils. In summary, our study uncovered a new mechanism by which CXCR4^hi neutrophils trigger sepsis-induced ALI by promoting NET formation, which is supported by PFKFB3-mediated glycolytic metabolism.

Keywords: ALI; CXCR4(hi) neutrophil; Glycolysis; NETs; PFKFB3; Sepsis.

MeSH terms

Acute Lung Injury* / metabolism
Animals
Extracellular Traps* / metabolism
Humans
Mice
Neutrophils / metabolism
Phosphofructokinase-2 / genetics
Phosphofructokinase-2 / metabolism
Receptors, CXCR4 / genetics
Sepsis* / complications
Signal Transduction

Substances

CXCR4 protein, human
PFKFB3 protein, human
Phosphofructokinase-2
Receptors, CXCR4