Blocking miR-212/132 in T cells is a potential therapy for treating colitis
Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, is thought to be caused by aberrant immune response to host intestinal microbiota, leading inflammation in gastrointestinal tract. The symptoms such as diarrhea, rectal bleeding, anemia, abdominal pain, or weight loss can be observed in the patients. Dysregulated T lymphocytes differentiation has been considered to be a trigger of IBD pathogenesis. Type 1 regulatory T (Tr1) cells producing IL-10, an anti-inflammatory subset of T lymphocytes, can prevent colitis. However, it remains unclear how Tr1 cell differentiation was controlled under intestinal inflammation.
Fig. 1. miR212/132 regulates Tr1 induction via c-maf expression.
MicroRNA is around 22nt non-cording RNA that binds 3’ untranslated region (3’UTR) of its target mRNAs, leading degradation and/or translational inhibition of these mRNAs. We previously reported that miR-212/132 expression is dependent on Aryl hydrocarbon receptor (Ahr). Recently, several groups showed that Ahr mediates suppressive immune response in IBD. In addition, it’s reported that Ahr positively regulates Tr1 cell induction via interacting with c-maf, a transcription factor for IL-10. On the basis of these findings, we hypothesize that Ahr-mediated miR-212/132 expression is involved in the pathogenesis of intestinal inflammation via regulating Tr1 cell generation.
In this study, we found that miR-212/132-KO mice are resistant to DSS-induced colitis, a mouse model of IBD with increased Tr1 cells. We found that lymphocytes isolated from colon of colitic mice abundantly express miR-212/132. Consistent with our previous findings, miR-212/132 expression was low in lymphocytes from colon of Ahr-KO mice. These results indicate that miR-212/132 is induced by Ahr under intestinal inflammation. To investigate the significance of Ahr-mediated miR-132/212 induction in intestinal inflammation, miR-212/132 KO mice and T cell-specific Ahr-deficient mice were subjected to DSS-induced colitis. Contrary to the observation in which Ahr KO mice show severe colitis, we found that miR-212/132 KO mice as well as T cell-specific Ahr-deficient mice exhibited less severe symptoms of the disease. In addition, the frequency of Tr1 cells in colon was significantly high in miR-212/132 KO mice, compared to that of control. Next, to examine whether miR-212/132 expression in T cells directly affects Tr1 cell differentiation, naïve T cells of miR-212/132 KO mice were cultured under Tr1 cell-polarizing condition. We found that Tr1 cell induction was significantly elevated by miR-212/132 loss. The computational analysis showed potential interaction between 3′-UTR of c-maf and miR-212/132. We found that c-maf expression was elevated at the protein level in miR-212/132-deficient T cells.
Our findings emphasize the important role of miR-212/132 in Tr1 cell differentiation under intestinal inflammation and suggest that inhibition of miR-212/132 represents a potential therapy for treating colitis.
Ichino Chinen1, Taisuke Nakahama2, Nam Trun Ngyen3 and Tadamitsu Kishimoto1
1Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka
2Laboratory of RNA Function, Graduate school of Medicine, Osaka University, Japan
3Vietnam Academy of Science and Technology, Institute of Biotechnology
Publication
The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis.
Chinen I, Nakahama T, Kimura A, Nguyen NT, Takemori H, Kumagai A, Kayama H, Takeda K, Lee S, Hanieh H, Ripley B, Millrine D, Dubey PK, Nyati KK, Fujii-Kuriyama Y, Chowdhury K, Kishimoto T
Int Immunol. 2015 Aug
Related Articles:
 | Muscle pain treated with injected normal saline solution Pain comes in all shapes and sizes. Ranging from acute to chronic, from nociceptive and myofascial to neuropathic, pain is a part of life. Myofascial or muscle pain, is among… |
 | miRNA, the inconspicuous but key player in the development… Cervical cancer is among the top three cancers affecting women below 45 years in several countries. Both the alterations and modification in deoxyribonucleic acid (DNA) sequences play a critical role… |
 | Maternal intake of resveratrol can help piglets resist early… Under commercial conditions, early weaning in pigs involves abrupt separation from sows, resulting in a sudden move to a new environment at a much younger age than would occur in… |
 | Bacillus coagulans Unique IS-2 helps ease symptoms of… Irritable bowel syndrome (IBS) is a common disorder that affects the digestive system. It is a mixture of abdominal pain and altered bowel frequency either constipation, diarrhoea or both (mixed).… |
 | Effectiveness of infrared tympanic thermometry during… Exposure to high solar radiation in the heat poses a thermoregulatory challenge and increased risks of exertional heat-related illness in workers and exercising individuals. Core temperature monitoring is important during… |
 | BioID screen for bacterial virulence proteins: new tools for… The discovery of penicillin in the 1920s revolutionized our ability to treat bacterial infection. However despite the introduction of antibiotics, infectious bacterial pathogens remain an immense challenge for the healthcare… |
Leave a Reply
You must be logged in to post a comment.