IRG1/ACOD1 promotes neutrophil reverse migration and alleviates local inflammation

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Polymorphonuclear neutrophils (PMNs) are key inflammatory cells.
• PMN reverse migration (rM) from inflammation sites is poorly understood.
• Understanding PMN rM is crucial for inflammation resolution.

Purpose of the Study:

• Investigate the mechanism of PMN rM.
• Determine the role of PMN rM in inflammation.
• Identify molecular regulators of PMN rM.

Main Methods:

• Lipopolysaccharide-induced acute lung inflammation mouse model.
• Single-cell RNA sequencing of PMNs.
• Mouse air pouch model for in vivo tracking.
• Irg1 knockout mouse studies.
• ICAM-1 and Cd11a neutralization experiments.

Main Results:

• Reverse migrated PMNs express high levels of immune-responsive gene 1 (Irg1/ACOD1).
• Irg1 knockout mice show reduced PMN rM and increased inflammation.
• Itaconate, an ACOD1 product, reduces PMN ICAM-1 expression.
• ICAM-1 and shed Cd11a binding retains PMNs; ACOD1 disrupts this interaction, promoting rM.

Conclusions:

• Irg1/ACOD1 plays a critical role in regulating PMN rM.
• PMN rM, facilitated by ACOD1, contributes to inflammation resolution.
• Targeting the ICAM-1/Cd11a axis may modulate PMN behavior in inflammation.