IL-25 Induced ROS-Mediated M2 Macrophage Polarization via AMPK-Associated Mitophagy

Int J Mol Sci. 2021 Dec 21;23(1):3. doi: 10.3390/ijms23010003.


Interleukin (IL)-25 is a cytokine released by airway epithelial cells responding to pathogens. Excessive production of reactive oxygen species (ROS) leads to airway inflammation and remodeling in asthma. Mitochondria are the major source of ROS. After stress, defective mitochondria often undergo selective degradation, known as mitophagy. In this study, we examined the effects of IL-25 on ROS production and mitophagy and investigated the underlying mechanisms. The human monocyte cell line was pretreated with IL-25 at different time points. ROS production was measured by flow cytometry. The involvement of mitochondrial activity in the effects of IL-25 on ROS production and subsequent mitophagy was evaluated by enzyme-linked immunosorbent assay, Western blotting, and confocal microscopy. IL-25 stimulation alone induced ROS production and was suppressed by N-acetylcysteine, vitamin C, antimycin A, and MitoTEMPO. The activity of mitochondrial complex I and complex II/III and the levels of p-AMPK and the mitophagy-related proteins were increased by IL-25 stimulation. The CCL-22 secretion was increased by IL-25 stimulation and suppressed by mitophagy inhibitor treatment and PINK1 knockdown. The Th2-like cytokine IL-25 can induce ROS production, increase mitochondrial respiratory chain complex activity, subsequently activate AMPK, and induce mitophagy to stimulate M2 macrophage polarization in monocytes.

Keywords: AMPK; IL-25; M2 macrophage polarization; mitophagy; reactive oxygen species.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetylcysteine / pharmacology
  • Antimycin A / pharmacology
  • Ascorbic Acid / pharmacology
  • Cell Polarity
  • Flow Cytometry
  • Humans
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Microscopy, Confocal
  • Mitochondria / metabolism*
  • Mitophagy
  • Monocytes / cytology*
  • Monocytes / metabolism
  • Organophosphorus Compounds / pharmacology
  • Phosphorylation / drug effects
  • Piperidines / pharmacology
  • Reactive Oxygen Species / metabolism*
  • THP-1 Cells


  • IL25 protein, human
  • Interleukin-17
  • MitoTEMPO
  • Organophosphorus Compounds
  • Piperidines
  • Reactive Oxygen Species
  • Antimycin A
  • AMP-Activated Protein Kinases
  • Ascorbic Acid
  • Acetylcysteine