A20 Mediated Regulation of Colitis and Spondyloarthritis

Investigator: Averil I. Ma, MD
Sponsor: NIH National Institute of Diabetes and Digestive and Kidney Diseases

Location(s): United States


Recent studies suggest that inflammatory bowel disease (IBD) results from the disruption of normal host immune cells responses to microbial molecules that can trigger inflammation in the intestine. Dendritic cells (DCs) are specialized immune cells that are highly sensitive to microbes and can potently activate inflammatory cells. As DCs may frequently or tonically sense the presence of microbes in the intestine, their propensity to cause inflammation may be dependent on their intracellular regulation or "interpretation" of encounters with microbes. Hence, intracellular proteins that regulate signals triggered by microbes may be central to the commitment to overt inflammatory responses. A20 is an enzyme that potently restricts signals from microbial sensing pathways, including Toll-like receptor (TLR), NOD and TNF signals. Thus, our central hypothesis is that A20 expression specifically in DCs preserves immune homeostasis and prevents IBD and IBD-associated arthritis. This project focuses on a novel anti-inflammatory protein called A20 and how it regulates dendritic cells, colitis, and colitis associated arthritis. Dendritc cells and Toll-like receptors are central to the pathogenesis of inflammatory bowel diseases. In addition, recent human genetic studies have revealed that SNPs of the human A20 gene are associated with Crohn's disease. Therefore, understandings how A20 regulates dendritic cells and prevents colitis and colitis associated arthritis will significantly enhance the development of therapies for inflammatory bowel diseases and have major benefits for public health.