Innate and Adaptive Interleukin-22 Protects Mice from Inflammatory Bowel Disease

Zenewicz, Lauren A.; Yancopouloš, George D.; Valenzuela, David M.; Murphy, Andrew J.; Stevens, Sean; Flavell, Richard A.

doi:10.1016/j.immuni.2008.11.003

Cited by 732 publications

(686 citation statements)

References 46 publications

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“…In addition, we identified a trend to fewer uNK cells in the decidua of patients with unexplained RPL compared to patients with a normal Research has shown that IL-22 can help constrain inflammation and protect mucosal sites, and that lower levels of IL-22 are associated with several inflammatory diseases, such as inflammatory bowel disease and acute graft-versus-host disease [18,19]. Additionally, it has been shown that, patients with worse symptoms and a prolonged disease course have significantly lower levels of IL-22 expression [18,19]. In this context, IL-22 likely plays a key role in maintaining decidual homeostasis and helps to constrain the inflammation common in early pregnancy.…”

Section: Resultsmentioning

confidence: 89%

Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Perfetto

Fan

Dahl

et al. 2015

J Assist Reprod Genet

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Purpose Researchers have hypothesized that an imbalance of immune cells in the uterine decidua and a dysfunction in cytokines they produce may contribute to recurrent pregnancy loss (RPL). The objective of this study was to determine if IL-22, IL-23 and IL-17 are expressed abnormally in the decidua of patients with RPL compared to those women with a normal pregnancy. We also sought to confirm that uterine natural killer (uNK) cells are lower in the decidua of patients with RPL, as well as identify IL-22 expression by uNK cells. Methods After meeting strict inclusion criteria, maternal decidua of nine patients with unexplained RPL and a confirmed euploid fetal loss, and 11 gestational age-matched patients undergoing elective pregnancy termination were included in our analysis. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to quantify RNA expression, Western blot was performed to quantify protein expression and immunohistochemistry (IHC) was performed to identify IL-22 and uNK cells. Results We found that women with unexplained RPL and a euploid fetal loss had significantly less gene and protein expression of IL-22 in the decidua. Additionally, we found that IL-22 is primarily expressed by uNK cells in the decidua. Conclusions In conclusion, our results suggest that lower levels of IL-22 in the uterine decidua in patients with unexplained RPL may contribute to a disruption of decidual homeostasis and ultimately lead to early pregnancy loss.

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Section: Resultsmentioning

confidence: 89%

Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Perfetto

Fan

Dahl

et al. 2015

J Assist Reprod Genet

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“…ILC3s are a group of lymphocytes without T‐cell‐specific antigen receptors with particular accumulation at mucosal sites and serve as key regulators during intestinal inflammation 18, 19, 20, 21. ILC3s can rapidly respond to external stimuli and play critical roles in host defense, the resolution of inflammation and initiation of tissue repair in the gut 21, 22, 23, 24, 25, 26. These protective effects of ILC3s are mostly dependent on their production of the reparative cytokine IL‐22.…”

Section: Introductionmentioning

confidence: 99%

“…These protective effects of ILC3s are mostly dependent on their production of the reparative cytokine IL‐22. By binding to its receptor on epithelial cells, IL‐22 contributes to production of antimicrobial peptides and mucins, regulation of gut microbiota, maintenance of the gut barrier function and amelioration of intestinal inflammation 25, 26. But it remains unclear how ILC3s are activated and regulated during intestinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

et al. 2018

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Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)–interleukin (IL)‐22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate (eATP) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL‐22‐producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL‐22. Mechanistically, activation of ILC3s for IL‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase‐mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine–ILC3 axis.

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“…The proinflammatory/pathological nature is apparent in mouse models with diseases such as psoriasis [4] and rheumatoid arthritis [22], and T. gondii infection [11]. In contrast, IL-22 plays protective roles and has tissue-protective and antimicrobial properties in several mouse models with diseases such as inflammatory bowel disease (IBD) [23], hepatitis [24] and infection with invading pathogenic bacteria [10,25,26].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Morishima

Mizoguchi

et al. 2011

Eur J Immunol

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IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting . Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19-and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-c and TNF-a. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.Key words: Hepatitis . IL-17 . IL-22 . IL-23Supporting Information available online Introduction IL-23 is a heterodimeric cytokine which belongs to the IL-6/IL-12 family and plays a key role in autoimmune and inflammatory disorders [1]. IL-23 acts on memory-type cells [2] and induces the production of . Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, . p19-deficient mice are highly resistant to the development of experimental allergic encephalomyelitis (EAE) [7], and it has been shown that the IL-23-dependent production of IL-17, but not , is important for the pathogenesis of autoimmune 2828diseases such as EAE [9]. Recent studies have also revealed that the IL-23-dependent production of IL-22, but not IL-17, plays a critical role in protection against subsequent infection. In infection with an attenuated strain of Salmonella enterica serovar Enteritidis, p19-deficient mice showed reduced survival and exacerbated liver necrosis only in the absence of IL-12 in an IL-17-independent manner [10]. In peroral infection with Toxoplasma gondii, which leads to the development of small intestine inflammation, the IL-23-dependent upregulation of IL-22 is essential for the development of ileitis; on the other hand, IL-17 is downregulated and dispensable [11].IL-22 is a member of the IL-10 cytokine family and plays important roles in inflammation, immune surveillance and tissue homeostasis [12][13][14][15] [10,25,26].Recently, we demonstrated that Notch, which is an evolutionally conserved molecule that controls cell fate decision in a variety of cells [27,28], drives IL-22 secretion by stimu...

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Innate and Adaptive Interleukin-22 Protects Mice from Inflammatory Bowel Disease

Cited by 732 publications

References 46 publications

Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

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