A novel role for TL1A/DR3 in protection against intestinal injury and infection

Jia, Li-Guo, Bamias, Giorgos, Burkly, Linda C., Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, Gruszka, D., Pizarro, T. T. and Cominelli, F. 2016. A novel role for TL1A/DR3 in protection against intestinal injury and infection. Journal of Immunology 197 (1) , pp. 377-386. 10.4049/​jimmunol.1502466 Item availability restricted.

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	The American Association of Immunologists
ISSN:	0022-1767
Date of First Compliant Deposit:	22 June 2016
Date of Acceptance:	30 April 2016
Last Modified:	07 Nov 2024 03:00
URI:	https://orca.cardiff.ac.uk/id/eprint/91052

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