HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury

J Immunol. 2022 Feb 15;208(4):968-978. doi: 10.4049/jimmunol.2100593. Epub 2022 Jan 21.


Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / etiology*
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology
  • Animals
  • Apoptosis / genetics
  • Biomarkers
  • Disease Models, Animal
  • Disease Susceptibility
  • Extracellular Traps / genetics*
  • HMGB1 Protein / genetics*
  • HMGB1 Protein / metabolism
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Neutrophils / immunology*
  • Neutrophils / metabolism*
  • Reperfusion Injury / etiology*
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology


  • Biomarkers
  • HMGB1 Protein
  • Myeloid Differentiation Factor 88