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Kang, J.S. The Role of IL-22 in Neuroinflammation. Encyclopedia. Available online: https://encyclopedia.pub/entry/18116 (accessed on 25 December 2025).
Kang JS. The Role of IL-22 in Neuroinflammation. Encyclopedia. Available at: https://encyclopedia.pub/entry/18116. Accessed December 25, 2025.
Kang, Jae Seung. "The Role of IL-22 in Neuroinflammation" Encyclopedia, https://encyclopedia.pub/entry/18116 (accessed December 25, 2025).
Kang, J.S. (2022, January 12). The Role of IL-22 in Neuroinflammation. In Encyclopedia. https://encyclopedia.pub/entry/18116
Kang, Jae Seung. "The Role of IL-22 in Neuroinflammation." Encyclopedia. Web. 12 January, 2022.
The Role of IL-22 in Neuroinflammation
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23020757

Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. The results in this entry demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.

IL-22 IL-22Rα inflammation BV2 HT22

1. Introduction

Interleukin (IL)-22, a member of the IL-10 cytokine family, is produced by several subsets of lymphocytes, including CD4 + T helper 17 (Th17) and Th22 cells, natural killer cells, CD8+ cytotoxic T cells, γδ T cells, and lymphoid tissue inducer-like cells [1][2][3][4][5]. In addition, it has been reported recently that IL-22 is also produced by activated macro-phages [6]. Although IL-22 has an anti-inflammatory role in inflammatory bowel diseases, it can promote inflammatory conditions in autoimmune diseases such as rheumatoid arthritis (RA), Crohn’s disease, and various skin diseases [7][8]. Also, IL-22 upregulates the production of acute-phase proteins in hepatoma cells, suggesting that it is involved in the regulation of inflammatory responses [4]. The biological role of IL-22 was originally described in hepatoma cells, keratinocytes, and pancreatic acinar cells, and it was subsequently reported to be involved in the pathogenesis of numerous inflammatory diseases, notably psoriasis [9][10][11].
The IL-22 receptor (IL-22R) is a heterodimer of IL-22Rα and IL-10Rβ subunits [5]. IL-10Rβ is expressed in a wide variety of cells, including immune cells, whereas IL-22Rα expression is thought to be limited to epithelial cells in organs such as the lung, kidney, colon, pancreas, and skin [4][12][13]. For this reason, the roles of IL-22Rα have typically been studied using non-hematopoietic organs [14]. These studies have shown that binding of IL-22 to IL-22Rα induces activation of Janus kinase 1 (JAK1), and the signal transducers and activators of transcription protein 3 (STAT3) and STAT5 pathways, as well as MAP kinase pathways such as the extracellular signal regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 pathways [2][15][16][17].

2. IL-22Rα Is Constitutively Expressed in BV2 Murine Microglial Cells, HT22 Hippocampal Neuronal Cells, and Mouse Brain Tissue

It is known that IL-22 shows its activity through the binding with IL-22R composed of IL-22Rα and IL-10Rβ. The expression of IL-22Rα is induced and increased under inflammatory condition. IL-10Rβ is constitutively expressed regardless with inflammation and plays a crucial role for signal transduction through IL-22R after dimerization with IL-22Rα. RT-PCR and Western blotting analyses revealed that IL-22Rα is expressed endogenously in BV2 murine microglial cells and HT22 hippocampal neuronal cells and IL-10Rβ is constitutively expressed (Figure 1A,B). A flow cytometry analysis also confirmed that IL-22Rα is expressed on the surface of BV2 and HT22 cells, as well as on that of Hepa1c1c7 murine hepatoma cells (used as a positive control; Figure 1C). In addition, an immunohistochemical analysis revealed that IL-22Rα is constitutively expressed in mouse brain tissues, especially the hippocampus and cerebellum, and its expression is increased by inflammation (Figure 1D). It is known that IL-22 shows its activity through the binding with IL-22R composed of IL-22Ra and IL-10Rb.
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Figure 1. IL-22Rα is constitutively expressed in BV2 and HT22 cells and mouse brain tissue. (A) RT-PCR analyses of IL-22Rα and IL-10Rβ in BV2 and HT22 cells. Total RNA was extracted from cells (1 × 106), and RT-PCR was performed using specific primers for IL-22Rα and IL-10Rβ, as described in the Materials and Methods. (B) Western blot analyses of IL-22Rα and IL-10Rβ in BV2 and HT22 cells. Protein was extracted from 1 × 106 cells and analyzed with -IL-22Rα Ab and anti-IL-10Rβ Ab, as described in the Materials and Methods. β-actin was used as a loading control. (C) Flow cytometry analyses of IL-22Rα in BV2, HT22, and Hepa1c1c7 cells. For each sample, 1 × 105 cells were collected, processed as described in the Materials and Methods, and then stained with an anti-mouse IL-22Rα antibody (2.5 µg/106 cells) as a primary antibody, and FITC-conjugated anti-rabbit Ab was used as a secondary antibody. IL-22Rα expression was analyzed as described in the Materials and Methods. (D) Immunohistochemical analysis of IL-22Rα expression in mouse brain. Paraffin-embedded tissues were sectioned with 4 μm thickness and incubated with a primary antibody against IL-22Rα and then with a biotinylated anti-rabbit antibody. ABC solution was loaded onto the sections for 30 min and a DAB kit was used for chromogenic detection. (A–D) Results are representative of three independent experiments.

3. The Interaction of IL-22 with IL-22Rα Induces Proinflammatory Cytokine Production in BV2 and HT22 Cells

Since IL-22 is an important pro-inflammatory cytokine, whether it induces the production of IL-6 and TNF-α in BV2 and HT22 cells were investigated via interaction with IL-22Rα [14]. As shown in Figure 2A, IL-22 treatment increased TNF-α production significantly in both cell lines. COX-2 is rarely expressed in steady state, but it is rapidly upregulated under inflammatory conditions. For this reason, the effects of IL-22 treatment (20 ng/mL) for 1, 3, 6, or 12 h on COX-2 mRNA expression in BV2 and HT22 cells were examined. RT-PCR analyses revealed that COX-2 mRNA expression was increased remarkably in both cell lines at 1 and 6 h after IL-22 treatment (Figure 2B). In addition, Western blotting analyses revealed that COX-2 protein levels were increased significantly in both cell lines 24 h after IL-22 treatment (Figure 2C). Next, the effect of exposure to IL-22 (20 ng/mL) for 12 or 24 h on PGE2 production was examined by ELISA. As expected, PGE2 production by BV2 and HT22 cells was increased significantly at 24 and 48 h after the treatment (Figure 2D). To examine whether IL-22 increases PGE2 production via the activation of COX-2, PGE2 production was measured after the treatment of NS-398, a specific inhibitor of COX-2, on both cells. As a result, the IL-22-induced increase in PGE2 production was attenuated by the treatment of NS-398 (Figure 2E).
Ijms 23 00757 g002 550
Figure 2. The interaction between IL-22 and IL-22Rα induces pro-inflammatory cytokine production in BV2 and HT22 cells. (A) ELISA-based analysis of TNF-α in the supernatants of BV2 and HT22 cells treated with or without IL-22 (20 ng/mL) for 24 or 48 h. ** p < 0.01; *** p < 0.001. (B) RT-PCR analysis of COX-2 expression in BV2 and HT22 cells treated with or without IL-22 (20 ng/mL) for 1, 3, 6, or 12 h. Relative intensity was analyzed by ImageJ software. All results were representative of at least three independent experiments. Values were presented as the mean ± SD. Significance (p-value) was determined by t-test, *** p < 0.001. (C) Western blot analysis of COX-2 expression in BV2 and HT22 cells treated with or without IL-22 (20 ng/mL) for 12 or 24 h. Relative intensity was analyzed by ImageJ software. * p < 0.05; ** p < 0.01; ns, not significant. (D) ELISA-based analysis of PGE2 in the supernatants of BV2 and HT22 cells treated with or without IL-22 (20 ng/mL) for 24 or 48 h. * p < 0.05; ** p < 0.01; *** p < 0.001. (E) ELISA-based analysis of PGE2 in the supernatants of BV2 and HT22 cells treated with or without IL-22 (20 ng/mL) and/or NS-398 (40 μM) for 24 h. ** p < 0.01; *** p < 0.001.

4. The JNK and STAT3 Signaling Pathways Play an Important Role in IL-22-Induced Proinflammatory Cytokine Production in BV2 and HT22 Cells, Respectively

To this end, BV2 and HT22 cells were pretreated with SP600125 (20 μM), a specific inhibitor of JNK, and with S3I-201 (50 μM), a specific inhibitor of STAT3, prior to treatment with IL-22. RT-PCR analyses revealed that SP600125 inhibited IL-22-induced TNF-α expression in BV2 cells, and that S3I-201 inhibited TNF-α expression in HT22 cells (Figure 3A). These findings were also confirmed by ELISA (Figure 3B). In addition, IL-22 treatment (20 ng/mL) increased the phosphorylation of JNK in BV2 cells (Figure 3C) and the phosphorylation of STAT3 (Figure 3D) in HT22 cells.
Ijms 23 00757 g003 550
Figure 3. The JNK and STAT3 signaling pathways play an important role in IL-22-mediated inflammatory cytokine production by BV2 and HT22 cells, respectively. (A) RT-PCR analyses of TNF-α in cells that were pretreated with DMSO (vehicle control), SP600125 (20 μM), and S3I-201 (50 μM) for 1 h prior to treatment with IL-22 (20 ng/mL) for 12 h. (B) ELISA-based analysis of TNF-α in the supernatants of cells that were pretreated with DMSO (vehicle control), SP600125 (20 μM), or and S3I-201 (50 μM) for 1 h prior to treatment with IL-22 (20 ng/mL) for 48 h. *** p < 0.001. (C) Immunoblot analyses of c-Jun and phosphorylated c-Jun in BV2 cells that were pretreated with SP600125 (20 μM) and then treated with IL-22 (20 ng/mL) for 0, 5, 10, 20, 30, or 60 min. Relative intensity was analyzed by ImageJ software. All results were representative of at least three independent experiments. Values were presented as the mean ± SD. Significance (p-value) was determined by t-test, *** p < 0.001. (D) Immunoblot analyses of STAT3 and phosphorylated STAT3 in HT22 cells that were pretreated with S3I-201 (50 μM) and then treated with IL-22 (20 ng/mL) for 0, 5, 10, 20, 30, or 60 min. (A,C,D) Results are representative of three independent experiments. Relative intensity was analyzed by ImageJ software. All results were representative of at least three independent experiments. Values were presented as the mean ± SD. Significance (p-value) was determined by t-test, *** p < 0.001.

5. IL-22Rα Expression Is Increased in the Gulo (-/-) Mouse Brain upon Inflammation

As shown in Figure 4A,B, IL-22Rα expression was increased in the cerebellum white matter region and the hippocampus CA1 region during the inflammatory response induced by vitamin C deficiency. These results suggest that inflammation induces IL-22Rα production in the cerebellum and hippocampus of Gulo (-/-) mice.
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Figure 4. IL-22Rα expression is increased in the Gulo (-/-) mouse brain upon inflammation. (A) Cerebellum. (B) Hippocampus, CA1 region is localized to the stratum pyramidal and apical dendritic arborization extending into the stratum radiatum. Immunohistochemical staining of the sagittal sections of the WT and 5 weeks Gulo (-/-) mouse brain and then paraffin-embedded tissues were sectioned with 4 μm thickness and incubated with a primary antibody against IL-22Rα and a biotinylated anti-rabbit antibody. Nuclei were counterstained with hematoxylin. Scale bar, 150 µm.

6. Conclusions

The findings indicate that IL-22Rα is spontaneously expressed in brain cells, especially microglia and hippocampal neurons, and is involved in the development of inflammatory responses following binding of its ligand IL-22.

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