Abstract
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.
Highlights
Interleukin (IL)-25 is an epithelial-derived cytokine that links innate and adaptive immunity by enhancing Th2 responses [1,2]
After PINK1 knockdown, the PINK1 downstream proteins (p-Parkin and LC3) were not affected by IL-25 treatment (Figure 5H,I). These results suggested that IL-25-induced mitophagy via PINK1-Parkin pathway through reactive oxygen species (ROS) and AMPK activation
To evaluate the functional outcomes of IL-25-induced mitophagy in THP-1 cells, we examined the effects of IL-25 on macrophage polarization
Summary
Interleukin (IL)-25 is an epithelial-derived cytokine that links innate and adaptive immunity by enhancing Th2 responses [1,2]. IL-25 is produced by immune cells and epithelial cells [3] It regulates the internal safety of adaptive immune responses, leading to the initiation of allergic diseases and playing a role in stimulating of pulmonary mucosal cells and fibroblasts [1,4]. IL-25 production in humans and mice or injection of IL-25 into animals has been shown to result in the secretion of high levels of Th2 cytokines, such as IL-4, IL-5, and IL-13 [5]. In a murine pulmonary fibrosis model, collagen deposition in the lungs of challenged mice was driven by IL-25-induced type 2 innate lymphoid cells (ILC2s)-released IL-13 [6]. IL-25 and ILC2s could be therapeutic targets of human fibrotic diseases
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