A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection.

Abstract

TNF-like cytokine 1A (TL1A) is expressed on APCs and provides costimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease. In the current study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways. We demonstrate that intact DR3 signaling protected mice from acute dextran sodium sulfate colitis because DR3(-/-) mice showed more severe mucosal inflammation and increased mortality. DR3(-/-) mice were compromised in their ability to maintain adequate numbers of CD4(+)CD25(+)Foxp3(+) regulatory T cells in response to acute mucosal damage. This defect in immune regulation led to a nonspecific upregulation of effector proinflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A(-/-) mice were similarly more susceptible to dextran sodium sulfate colitis, although without mortality and with delayed kinetics compared with DR3(-/-) mice, and also displayed significantly reduced numbers of regulatory T cells. Infection of DR3(-/-) mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation.

• Authors: Li-Guo Jia, Giorgos Bamias, Kristen O Arseneau, Linda C Burkly, Eddy C Y Wang, Dennis Gruszka, Theresa T Pizarro, Fabio Cominelli
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 197 Issue 1 Pg. 377-86 (07 01 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27233964 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Receptors, Tumor Necrosis Factor, Member 25
• Tnfrsf25 protein, mouse
• Tnfsf15 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 15
• Dextran Sulfate

Topics

• Animals
• Cells, Cultured
• Colitis (immunology)
• Dextran Sulfate
• Forkhead Transcription Factors (metabolism)
• Humans
• Intestines (microbiology, pathology)
• Mice
• Mice, Knockout
• Mice, SCID
• Receptors, Tumor Necrosis Factor, Member 25 (genetics, metabolism)
• Salmonella Infections (immunology)
• Salmonella typhimurium (immunology)
• Signal Transduction (genetics)
• T-Lymphocytes, Regulatory (immunology)
• Th17 Cells (immunology)
• Tumor Necrosis Factor Ligand Superfamily Member 15 (genetics, metabolism)