A Newly Identified Role for Interleukin-22 in Bladder Immunity

INTRODUCTION AND OBJECTIVES: Bacterial and parasitic urinary tract infections(UTI) plague many children and yet our understanding of immunity to these pathogens remains poor. Recent data indicates that during infection of other epithelial organs, interleukin-22(IL-22) is a key cytokine for epithelial immunity. We hypothesized that IL-22 would prove crucial during UTI.

METHODS: IL-22-null (KO) and wild type (wt) mice underwent bladder wall injection with S. haematobium eggs or transurethral infection with type 1 piliated uropathogenic E. coli UTI89. Bladder RNA and protein expression was analyzed by qPCR and microarrays and immunofluorescence, and infiltrating cells characterized by flow cytometry. Urine, bladder, and kidney cfu were measured in UTI89-infected mice.

RESULTS: Levels of IL-22 and its soluble binding protein, IL-22BP, were increased in the bladder after exposure to S. haematobium eggs. Genes typically induced by IL-22 (CXCL2, REG3G[antimicrobial defense protein]], S100A8, S100A9, and Areg) were expressed at higher levels after S. haematobium egg injection. IL-22 stimulation of bladder tissue and the MBT-2 bladder cancer cell line induce expression of the antimicrobial proteins REG3B and REG3G. IL-22 receptor α1 expression was detectable in the urothelium by immunofluorescence and qPCR. Injection of S. haematobium eggs into IL-22-KO vs wt mice resulted in differential expression of genes related to glutathione transferase activity, transferase activity(transferring alkyl or aryl groups), and epithelial cell development. Numerous genes for the uroplakins were downregulated in egg-injected, IL-22-KO mice relative to their wt counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL22 is important for replenishing the epithelial lining during infection-related injury. IL-22-KO and wild-type littermate mice were transurethrally infected with UTI89. FimH is a principal adhesin used by type I piliated bacteria like UTI89 to bind to the uroplakin receptor complex of mature urothelial cells, permitting colonization of the urothelium during UTI. IL-22-KO mice had lower bacterial counts in their urine, bladder, and kidneys. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to higher kidney bacterial counts and increased morbidity.

CONCLUSIONS: Our data suggest that IL-22 is indeed important in urinary tract immunity, and may interfere with clearance of bacteria from the urinary tract, potentially through its role in maintenance of mature urothelium.

Jared Honeycutt, Stanford, CA, Michael Hsieh, Washington, DC. 

Published in The Society for Paediatric Urology, 15 May 2015

Protective effect of Th22 cells and intrahepatic IL-22 in drug induced hepatocellular injury

A positive correlation between intrahepatic IL-22 level and liver regeneration was observed in drug induced liver injury (DILI)  onset patients. Plasma IL-22 level was higher in drug induced liver injury patients with improved liver function than unimproved function. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.

Published in Journal of Hepatology Volume 63 Issue 1, July 2015, Pages 148–155

Interferon and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection

The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon- (IFN-), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-, both of which were ‘preferentially’ expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons. 

Published in Nature Immunology online 25 May 2015 

Crotoxin from Crotalus durissus terrificus Is Able to Down-Modulate the Acute Intestinal Inflammation in Mice

Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. The modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS) with CTX administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice.

Published in PLOS  April 8, 2015

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