MicroRNAs (miRNA), a class of small non-coding RNAs, are emerging as important regulators of gene expression in the immune system by functioning as endogenous inhibitors of translational processes by binding to the 3'-UTR of target genes. There is increasing evidence that miRNAs function as an effective system to regulate the magnitude of inflammatory responses and have been associated with the pathogenesis of various human diseases. We have established recently that miR-10a, conserved in both mouse and human spp, was highly expressed in intestine dendritic cells (DC), and negatively regulated by microbiota through the interaction of TLR-TLR ligands via the MyD88 pathway. We identified IL-12/IL-23p40, which is shared by IL-12 and IL-23, two important cytokines in the pathogenesis of inflammatory bowel disease, as a target gene of miR-10a, in that miR-10a directly bound to the 3'-UTR of the IL-12/IL-23p40 gene, and overexpression of miR-10a inhibited DC IL-12/IL-23p40 expression and production of IL-12 and IL-23. miR-10a expression was decreased in the inflamed intestinal lesions in mice with colitis, which was correlated with high levels of IL- 12 and IL-23, compared to that in normal mice. A recent report further demonstrated that miR-10a attenuated regulatory T cell (Treg) conversion into effector T cells and inhibited Th17 differentiation. In the present proposal, our preliminary data demonstrate that miR-10a expression is decreased in intestinal biopsies of patients with Crohn's disease (CD) and ulcerative colitis (UC), when compared to its expression in normal individuals, a finding that is indicative of the relevance of dysregulated miR-10a to human IBD. NFkB activation is elevated in IBD patients and localizes primarily in the intestines to lamina propria dendritic and epithelial cells. Overexpression of miR-10a suppresses DC expression of NFkB activation and TNFa production and inhibits colitis development in an animal model. In this project, we will investigate the regulatory targets of miR-10a in mucosal DC, and the mechanisms of how miR-10a expression regulates mucosal DC activation and function in response to microbiota. Lastly, we will test our hypothesis that DC expression of miR-10a shifts mucosal T cell responses to low levesl of Th1/Th17 and high levels of Treg, which leads to preservation of intestinal immune homeostasis and prevention of inflammatory bowel disease.

Public Health Relevance

Inflammatory bowel diseases (IBD) are diseases of immune dysregulation, and several types of immune cells, including dendritic cells and T lymphocytes, play crucial roles in the pathogenesis of IBD. Recently discovered small molecules, called microRNA, are important in controlling the function of dendritic cell and T lymphocytes, and we found that one of these microRNAs, called microRNA-10a, regulates intestinal response to gut bacteria. This proposal will address whether and how microRNA-10a regulates host dendritic cell and T lymphocyte response to gut bacteria to protect the intestines from inflammation and what it means to IBD pathogenesis to identify the potential pathways that can lead to development of a successful therapy for established IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK098370-01A1
Application #
8631732
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2013-09-16
Project End
2017-08-31
Budget Start
2013-09-16
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$336,038
Indirect Cost
$118,538
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Cao, Anthony T; Yao, Suxia; Stefka, Andrew T et al. (2014) TLR4 regulates IFN-? and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation. J Leukoc Biol 96:895-905
Xue, Xiaochang; Cao, Anthony T; Cao, Xiaocang et al. (2014) Downregulation of microRNA-107 in intestinal CD11c(+) myeloid cells in response to microbiota and proinflammatory cytokines increases IL-23p19 expression. Eur J Immunol 44:673-82
Liu, Zhanju; Cao, Anthony T; Cong, Yingzi (2013) Microbiota regulation of inflammatory bowel disease and colorectal cancer. Semin Cancer Biol 23:543-52