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. 2021 Mar 12:2021:6621296.
doi: 10.1155/2021/6621296. eCollection 2021.

Interleukin-22 Plays a Protective Role by Regulating the JAK2-STAT3 Pathway to Improve Inflammation, Oxidative Stress, and Neuronal Apoptosis following Cerebral Ischemia-Reperfusion Injury

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Interleukin-22 Plays a Protective Role by Regulating the JAK2-STAT3 Pathway to Improve Inflammation, Oxidative Stress, and Neuronal Apoptosis following Cerebral Ischemia-Reperfusion Injury

Yongfei Dong et al. Mediators Inflamm. .

Abstract

The interleukins (ILs) are a pluripotent cytokine family that have been reported to regulate ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. IL-22 is a member of the IL-10 superfamily and plays important roles in tissue injury and repair. However, the effects of IL-22 on ischemic stroke and cerebral I/R injury remain unclear. In the current study, we provided direct evidence that IL-22 treatment decreased infarct size, neurological deficits, and brain water content in mice subjected to cerebral I/R injury. IL-22 treatment remarkably reduced the expression of inflammatory cytokines, including IL-1β, monocyte chemotactic protein- (MCP-) 1, and tumor necrosis factor- (TNF-) α, both in serum and the ischemic cerebral cortex. In addition, IL-22 treatment also decreased oxidative stress and neuronal apoptosis in mice after cerebral I/R injury. Moreover, IL-22 treatment significantly increased Janus tyrosine kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 phosphorylation levels in mice and PC12 cells, and STAT3 knockdown abolished the IL-22-mediated neuroprotective function. These findings suggest that IL-22 might be exploited as a potential therapeutic agent for ischemic stroke and cerebral I/R injury.

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Conflict of interest statement

No conflicts of interests are declared by the authors.

Figures

Figure 1
Figure 1
IL-22 treatment ameliorated cerebral I/R injury. (a) Representative sections of TTC staining in each group (n = 6). (b) Quantification of infarct volume in each group (n = 6). (c) Neurological deficits were assessed in each group (n = 8). (d) Brain water content was calculated in each group (n = 6). P < 0.05 vs sham group; #P < 0.05 vs MCAO group.
Figure 2
Figure 2
IL-22 treatment inhibited the inflammatory response after cerebral I/R injury. Serum levels of IL-1β (a), MCP-1 (b), and TNF-α (c) were measured by ELISA (n = 8). The mRNA expression of IL-1β (d), MCP-1 (e), and TNF-α (f) was detected in brain tissues (n = 8). P < 0.05 vs. sham group; #P < 0.05 vs. MCAO group.
Figure 3
Figure 3
IL-22 treatment attenuated oxidative stress and neuronal apoptosis after cerebral I/R injury. The levels of SOD (a), GSH (b), and MDA (c) were detected in brain tissues (n = 6). (d) Neuronal apoptosis was detected by TUNEL staining combined with immunostaining for NeuN (n = 5, scale bar = 75 μm). P < 0.05 vs. sham group; #P < 0.05 vs. MCAO group.
Figure 4
Figure 4
IL-22 treatment inhibited OGD/R-induced inflammation and oxidative stress. The mRNA expression of IL-1β (a), MCP-1 (b), and TNF-α (c) was detected in PC12 cells (n = 6). The levels of SOD (d), GSH (e), and MDA (f) were detected in PC12 cells (n = 6). P < 0.05 vs. PBS group; #P < 0.05 vs. OGD/R group.
Figure 5
Figure 5
IL-22 treatment attenuated OGD/R-induced neuronal apoptosis. (a) Neuronal apoptosis was detected by TUNEL staining (n = 5, scale bar = 50 μm). (b) The expression of Bax, Bcl-2, and β-actin was detected by western blotting (n = 4). P < 0.05 vs. PBS group; #P < 0.05 vs. OGD/R group.
Figure 6
Figure 6
IL-22 treatment activated the JAK2/STAT3 signaling pathway. (a) The expression of p-JAK2, JAK2, p-STAT3, STAT3, and β-actin in the brain was detected by western blotting (n = 4). (b) The expression of p-JAK2, JAK2, p-STAT3, STAT3, and β-actin in PC12 cells was detected by western blotting (n = 4). P < 0.05 vs. the sham or PBS group; #P < 0.05 vs. the MCAO or OGD/R group.
Figure 7
Figure 7
JAK2 and STAT3 knockdown abolished IL-22-mediated neuroprotection. The mRNA expression of IL-1β (a), MCP-1 (b), and TNF-α (c) was detected in PC12 cells (n = 6). The levels of SOD (d), GSH (e), and MDA (f) were detected in PC12 cells (n = 6). (g) The expression of Bax, Bcl-2, and β-actin was detected by western blotting (n = 4). P < 0.05 vs. PBS group; #P < 0.05 vs. OGD/R group; &P < 0.05 vs. OGD/R+rIL-22 group.

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