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. To test our central hypothesis, we have generated a novel strain of mice, A20FL/FL CD11c-Cre mice, in which A20 is deleted specifically from DCs. Remarkably;our preliminary data with these mice suggest that these mice spontaneously develop colitis, sero-negative arthritis and spondyloarthritis, a stereotypical syndrome in human IBD. We now propose to use these A20FL/FL CD11-cre mice to determine the cellular and molecular mechanisms linking A20 expression in DCs to these provocative phenotypes. Specifically, we will determine whether luminal microbes and T cells are involved in the pathophysiologies by which A20 deficient DCs cause colitis and arthritis (Aim 1). As A20 may restrict intracellular signals in DCs, including MyD88 dependent TLR signals, we will use compound A20FL/FL MyD88FL/FL CD11c-Cre mice to determine which A20 regulated signals in DCs are MyD88-dependent and which signals are MyD88-independent. Studies with these mice will unveil which intracellular DC signals and DC products regulate T cell activation, colitis, and sero-negative arthritis (Aim 2). A20 is a ubiquitn modifying enzyme that regulates ubiquitination of signaling proteins and also binds to A20 Binding Inhibitor of NFkB-1, or ABIN-1. To define the molecular mechanisms by which A20 and ABIN-1 may collaborate to restrict signals in DCs, we have also generated mice lacking ABIN-1 specifically in DCs. We will now use these mice to study how ABIN-1 collaborates with A20 to restrict signaling in DCs and prevent colitis and arthritis (Aim 3).
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.
|Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:618-27|
|Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) Erratum: The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:785|
|Ma, Averil (2015) From trash collectors to guardians of cell signaling and immune homeostasis. Immunol Rev 266:1-5|
|Duong, Bao H; Onizawa, Michio; Oses-Prieto, Juan A et al. (2015) A20 restricts ubiquitination of pro-interleukin-1Î² protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42:55-67|
|Tiruppathi, Chinnaswamy; Soni, Dheeraj; Wang, Dong-Mei et al. (2014) The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nat Immunol 15:239-47|
|Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91|
|Shao, Ling; Oshima, Shigeru; Duong, Bao et al. (2013) A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis. PLoS One 8:e62223|
|Garg, Abhishek V; Ahmed, Mushtaq; Vallejo, Abbe N et al. (2013) The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling. Sci Signal 6:ra44|
|Callahan, Joseph A; Hammer, Gianna E; Agelides, Alexander et al. (2013) Cutting edge: ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells. J Immunol 191:535-9|
|Ma, Averil; Malynn, Barbara A (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774-85|
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