International Journal of Molecular Sciences

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13 pages, 4822 KiB

Open AccessArticle

Preventive Effect of Vitamin C on Dextran Sulfate Sodium (DSS)-Induced Colitis via the Regulation of IL-22 and IL-6 Production in Gulo(−/−) Mice

by Hyejung Jo, Dahae Lee, Cheolhyeon Go, Yoojin Jang, Naghyung Chu, Suhyun Bae, Dongmin Kang, Jong Pil Im, Yejin Kim and Jae Seung Kang

Int. J. Mol. Sci. 2022, 23(18), 10612; https://doi.org/10.3390/ijms231810612 - 13 Sep 2022

Cited by 8 | Viewed by 2407

Abstract

Reactive oxygen species (ROS), which are exceptionally high in IBD lesions, are known to cause abnormal immune responses to inflammatory reactions in inflammatory bowel diseases (IBD) through damage to the intestinal mucosal linings. Moreover, they are theorized to be an agent of IBD [...] Read more.

Reactive oxygen species (ROS), which are exceptionally high in IBD lesions, are known to cause abnormal immune responses to inflammatory reactions in inflammatory bowel diseases (IBD) through damage to the intestinal mucosal linings. Moreover, they are theorized to be an agent of IBD development. Vitamin C is widely known to be an effective antioxidant for its ability to regulate inflammatory responses through its ROS scavenging effect. Therefore, we examined vitamin C’s influence on the development and progression of IBD in Gulo(−/−) mice, which cannot synthesize vitamin C like humans due to a defect in the expression of L-gulono-γ–lactone oxidase, an essential enzyme for vitamin C production. First, we found extensive oxidative stress and an inflammation increase in the colon of vitamin C-insufficient Gulo(−/−) mice. We also found decreased IL-22 production and NKp46(+) cell recruitment and the impaired activation of the p38MAPK pathway. Additionally, comparing vitamin C-insufficient Gulo(−/−) mice to vitamin C-sufficient Gulo(−/−) mice and wild-type mice, the insufficient group faced a decrease in mucin-1 expression, accompanied by an increase in IL-6 production, followed by the activation of the STAT3 and Akt pathways. The results suggest that vitamin C insufficiency induces severe colitis, meaning vitamin C could also take on a preventative role by regulating the production of cytokines and the induction of inflammation. Full article

(This article belongs to the Special Issue Interleukin 22)

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16 pages, 1558 KiB

Open AccessArticle

IgG from Adult Atopic Dermatitis (AD) Patients Induces Nonatopic Neonatal Thymic Gamma–Delta T Cells (γδT) to Acquire IL-22/IL-17 Secretion Profile with Skin-Homing Properties and Epigenetic Implications Mediated by miRNA

by Beatriz Oliveira Fagundes, Thamires Rodrigues de Sousa, Andrezza Nascimento, Lorena Abreu Fernandes, Fábio da Ressureição Sgnotto, Raquel Leão Orfali, Valéria Aoki, Alberto José da Silva Duarte, Sabri Saeed Sanabani and Jefferson Russo Victor

Int. J. Mol. Sci. 2022, 23(12), 6872; https://doi.org/10.3390/ijms23126872 - 20 Jun 2022

Cited by 10 | Viewed by 2988

Abstract

γδT cells mature in the human thymus, and mainly produce IL-17A or IFN-γ, but can also produce IL-22 and modulate a variety of immune responses. Here, we aimed to evaluate whether IgG from AD patients (AD IgG) can functionally modulate thymic nonatopic γδT [...] Read more.

γδT cells mature in the human thymus, and mainly produce IL-17A or IFN-γ, but can also produce IL-22 and modulate a variety of immune responses. Here, we aimed to evaluate whether IgG from AD patients (AD IgG) can functionally modulate thymic nonatopic γδT cells. Thymic tissues were obtained from 12 infants who had not had an atopic history. Thymocytes were cultured in mock condition, or in the presence of either AD IgG or therapeutic intravenous IgG (IVIg). Following these treatments, intracellular cytokine production, phenotype, and microRNA expression profiles were investigated. AD IgG could downregulate α4β7, upregulate CLA, and induce the production of IFN-γ, IL-17, and IL-22 in γδT cells. Although both AD IgG and IVIg could directly interact with γδT cell membranes, AD IgG could reduce γδT cell apoptosis. AD IgG could upregulate nine miRNAs compared to IVIg, and six when compared to the mock condition. In parallel, some miRNAs were downregulated. Target gene prediction and functional analysis indicated that some target genes were enriched in the negative regulation of cellular transcription. This study shows that AD IgG influences the production of IL-17 and IL-22 by intrathymic nonatopic γδT cells, and demonstrates epigenetic implications mediated by miRNAs. Full article

(This article belongs to the Special Issue Interleukin 22)

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18 pages, 1677 KiB

Open AccessArticle

IgG from Adult Atopic Dermatitis (AD) Patients Induces Thymic IL-22 Production and CLA Expression on CD4+ T Cells: Possible Epigenetic Implications Mediated by miRNA

by Thamires Rodrigues de Sousa, Beatriz Oliveira Fagundes, Andrezza Nascimento, Lorena Abreu Fernandes, Fábio da Ressureição Sgnotto, Raquel Leão Orfali, Valéria Aoki, Alberto José da Silva Duarte, Sabri Saeed Sanabani and Jefferson Russo Victor

Int. J. Mol. Sci. 2022, 23(12), 6867; https://doi.org/10.3390/ijms23126867 - 20 Jun 2022

Cited by 9 | Viewed by 2999

Abstract

Atopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD [...] Read more.

Atopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD patients could modulate the thymic maturation of IL-22-producing T cells and CLA+ T cells of non-atopic infants. Given that miRNAs regulate immune response genes, we evaluated whether miRNA expression is also altered in cultured thymocytes. Thymocytes were cultured with purified IgG from AD patients or control conditions (mock, Intravenous-IgG (IVIg), non-atopic IgG, or atopic non-AD IgG). Using flow cytometry analysis, we assessed the expression of CLA and intracellular levels of IL-4, IFN-γ, and IL-22 on double-positive T cells (DP T), CD4 T cells, or CD8 T cells. We also investigated the frequency of IgG isotypes and their direct interaction with the thymic T cells membrane. The miRNA profiles were evaluated by the Illumina small RNA-seq approach. MiRNA target gene prediction and enrichment analyses were performed using bioinformatics. Increased frequencies of IL-22 and CLA+ producing CD4+ T cells cultured with IgG of AD patients was seen in non-atopic infant thymocytes compared to all control conditions. No alterations were observed in the frequency of IgG isotypes among evaluated IgG pools. Evidence for a direct interaction between IgG and thymic DP T, CD4 T, and CD8 T cells is presented. The small RNA-seq analysis identified ten mature miRNAs that were modulated by AD IgG compared to mock condition (miR-181b-5p, hsa-miR-130b-3p, hsa-miR-26a-5p, hsa-miR-4497, has-miR-146a, hsa-let-7i-5p, hsa-miR-342-3p, has-miR-148a-3p, has-miR-92a and has-miR-4492). The prediction of the targetome of the seven dysregulated miRNAs between AD and mock control revealed 122 putative targets, and functional and pathway enrichment analyses were performed. Our results enhance our understanding of the mechanism by which IgG can collaborate in thymic T cells in the setting of infant AD. Full article

(This article belongs to the Special Issue Interleukin 22)

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22 pages, 4350 KiB

Open AccessArticle

Intestinal Radiation Protection and Mitigation by Second-Generation Probiotic Lactobacillus-reuteri Engineered to Deliver Interleukin-22

by Alexis Espinal, Michael W. Epperly, Amitava Mukherjee, Renee Fisher, Donna Shields, Hong Wang, M. Saiful Huq, Diala Fatima Hamade, Anda M. Vlad, Lan Coffman, Ronald Buckanovich, Jian Yu, Brian J. Leibowitz, Jan-Peter van Pijkeren, Ravi B. Patel, Donna Stolz, Simon Watkins, Asim Ejaz and Joel S. Greenberger

Int. J. Mol. Sci. 2022, 23(10), 5616; https://doi.org/10.3390/ijms23105616 - 17 May 2022

Cited by 14 | Viewed by 3806

Abstract

(1) Background: The systemic administration of therapeutic agents to the intestine including cytokines, such as Interleukin-22 (IL-22), is compromised by damage to the microvasculature 24 hrs after total body irradiation (TBI). At that time, there is significant death of intestinal microvascular endothelial cells [...] Read more.

(1) Background: The systemic administration of therapeutic agents to the intestine including cytokines, such as Interleukin-22 (IL-22), is compromised by damage to the microvasculature 24 hrs after total body irradiation (TBI). At that time, there is significant death of intestinal microvascular endothelial cells and destruction of the lamina propria, which limits drug delivery through the circulation, thus reducing the capacity of therapeutics to stabilize the numbers of Lgr5+ intestinal crypt stem cells and their progeny, and improve survival. By its direct action on intestinal stem cells and their villus regeneration capacity, IL-22 is both an ionizing irradiation protector and mitigator. (2) Methods: To improve delivery of IL-22 to the irradiated intestine, we gavaged Lactobacillus-reuteri as a platform for the second-generation probiotic Lactobacillus-reuteri-Interleukin-22 (LR-IL-22). (3) Results: There was effective radiation mitigation by gavage of LR-IL-22 at 24 h after intestinal irradiation. Multiple biomarkers of radiation damage to the intestine, immune system and bone marrow were improved by LR-IL-22 compared to the gavage of control LR or intraperitoneal injection of IL-22 protein. (4) Conclusions: Oral administration of LR-IL-22 is an effective protector and mitigator of intestinal irradiation damage. Full article

(This article belongs to the Special Issue Interleukin 22)

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15 pages, 2739 KiB

Open AccessArticle

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

by Dahae Lee, Hyejung Jo, Cheolhyeon Go, Yoojin Jang, Naghyung Chu, Suhyun Bae, Dongmin Kang, Yejin Kim and Jae Seung Kang

Int. J. Mol. Sci. 2022, 23(2), 757; https://doi.org/10.3390/ijms23020757 - 11 Jan 2022

Cited by 18 | Viewed by 3151

Abstract

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. Although IL-22 is [...] Read more.

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. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain. Full article

(This article belongs to the Special Issue Interleukin 22)

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13 pages, 2059 KiB

Open AccessArticle

Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product

by Hendrik Stülb, Malte Bachmann, Sina Gonther and Heiko Mühl

Int. J. Mol. Sci. 2021, 22(19), 10623; https://doi.org/10.3390/ijms221910623 - 30 Sep 2021

Cited by 7 | Viewed by 2759

Abstract

Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 [...] Read more.

Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders. Full article

(This article belongs to the Special Issue Interleukin 22)

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15 pages, 2342 KiB

Open AccessArticle

Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker

by Julie Rae, Jason Hackney, Kevin Huang, Mary Keir and Ann Herman

Int. J. Mol. Sci. 2021, 22(15), 8205; https://doi.org/10.3390/ijms22158205 - 30 Jul 2021

Cited by 2 | Viewed by 2851

Abstract

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line [...] Read more.

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1β. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1β suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22. Full article

(This article belongs to the Special Issue Interleukin 22)

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13 pages, 592 KiB

Open AccessReview

The Role of IL-22 in Wound Healing. Potential Implications in Clinical Practice

by Roxana Delia Zaharie, Călin Popa, Diana Schlanger, Dan Vălean and Florin Zaharie

Int. J. Mol. Sci. 2022, 23(7), 3693; https://doi.org/10.3390/ijms23073693 - 28 Mar 2022

Cited by 19 | Viewed by 2255

Abstract

Wound healing is a complex process that is mediated and influenced by several cytokines, chemokines, and growth factors. Interleukin-22 (IL-22) is a cytokine that plays a critical role in tissue regeneration. Our study is a systematic review that addressed the implications of IL-22 [...] Read more.

Wound healing is a complex process that is mediated and influenced by several cytokines, chemokines, and growth factors. Interleukin-22 (IL-22) is a cytokine that plays a critical role in tissue regeneration. Our study is a systematic review that addressed the implications of IL-22 in the healing of wounds caused by external factors. Thirteen studies were included in our review, most of them being experimental studies. Three clinical studies underlined the potential role of IL-22 in day-to-day clinical practice. IL-22 plays a central role in wound healing, stimulating the proliferation, migration, and differentiation of the cells involved in tissue repair. However, overexpression of IL-22 can cause negative effects, such as keloid scars or peritoneal adhesions. The results of the presented studies are promising, but further research that validates the roles of IL-22 in clinical practice and analyzes its potential implication in surgical healing is welcomed. Full article

(This article belongs to the Special Issue Interleukin 22)

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