IRG1/ACOD1 promotes neutrophil reverse migration and alleviates local inflammation

Jingjing Ji*, Hanhui Zhong, Yuehua Li, Timothy R. Billiar, Mark A. Wilson, Melanie J. Scott, Jie Fan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Polymorphonuclear neutrophil (PMN) infiltration at inflammatory site plays a critical role in inflammation. PMN reverse migration (rM) describes the phenomenon that PMNs migrate away from inflammatory site back into the vasculature, and its role within inflammatory scenarios remains to be fully determined. This study aimed to investigate the mechanism underlying PMN rM and its role in inflammation. First, we demonstrated PMN rM in a mouse model of lipopolysaccharide-induced acute lung inflammation. By single-cell RNA sequencing, we demonstrated that reverse migrated (rM-ed) PMNs in blood expressed a high level of immune-responsive gene 1 (Irg1), the encoding gene of cis-aconitate decarboxylase (ACOD1). Using a mouse air pouch model, which enabled us to directly track rM-ed PMNs in vivo, we detected higher expression of ACOD1 in the rM-ed PMNs in circulation. Furthermore, mice with Irg1 knockout exhibited decreased PMN rM and higher levels of inflammatory cytokine in inflammatory site. Mechanistically, we found that itaconate, the product of ACOD1 catalyzation, decreased PMN ICAM-1 expression at the inflammation site. Furthermore, inflammatory site showed a high level of shed Cd11a, the ligand of ICAM-1. Neutralization of either ICAM-1 or Cd11a led to increased PMN rM. These findings suggest that the binding of ICAM-1 and shed Cd11a serves as a retaining force to hold PMNs in the site of inflammation, and ACOD1-decreased PMN surface expression of ICAM-1 weakens the retaining force, promoting PMNs to leave the inflammatory site. These results indicate a regulatory role of IRG1 in PMN rM and subsequent contributions to inflammation resolution.

Original languageEnglish
Pages (from-to)854-863
Number of pages10
JournalJournal of Leukocyte Biology
Volume116
Issue number4
DOIs
StatePublished - 1 Oct 2024
Externally publishedYes

Keywords

  • ICAM-1
  • IRG1
  • cd11a
  • itaconate
  • neutrophil reverse migration

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