Death Receptor 3 promotes chemokine directed leukocyte recruitment in acute resolving inflammation and is essential for pathological development of mesothelial fibrosis in chronic disease

William V. Perks, Ravinder K. Singh, Gareth Wyn Jones, Jason Peter Twohig, Anwen Sian Williams, Ian R. Humphreys, Philip Russel Taylor, Simon Arnett Jones, Eddie Chung Yern Wang

Research output: Contribution to journalArticle (Academic Journal)

Abstract

Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factorelike ligand TL1A (TNFSF15) control several processes in inflammatory diseases through the expansion of effector T cells and the induction of proinflammatory cytokines from myeloid and innate lymphoid cells. Using wild-type (DR3þ/þ) and DR3-knockout (DR3/) mice, we show that the DR3/TL1A pathway triggers the release of multiple chemokines after acute peritoneal inflammation initiated by a single application of Staphylococcus epidermidis supernatant, correlating with the infiltration of multiple leukocyte subsets. In contrast, leukocyte infiltration was not DR3 dependent after viral challenge with murine cytomegalovirus. DR3 expression was recorded on connective tissue stroma, which provided DR3-dependent release of chemokine (C-C motif) ligand (CCL) 2, CCL7, CXCL1, and CXCL13. CCL3, CCL4, and CXCL10 production was also DR3 dependent, but quantitative RT-PCR showed that their derivation was not stromal. In vitro cultures identified resident macrophages as a DR3-dependent source of CCL3. Whether DR3 signaling could contribute to a related peritoneal pathology was then tested using multiple applications of S. epidermidis supernatant, the repetitive inflammatory episodes of which lead to peritoneal membrane thickening and collagen deposition. Unlike their DR3þ/þ counterparts, DR3/ mice did not develop fibrosis of the mesothelial layer. Thus, this work describes both a novel function and essential requirement for the DR3/TL1A pathway in acute, resolving, and chronic inflammation in the peritoneal cavity. (Am J Pathol 2016, 186: 2813e2823; http://dx.doi.org/10.1016/j.ajpath.2016.07.021)
Original languageEnglish
Pages (from-to)2813-2823
Number of pages11
JournalAmerican Journal of Pathology
Volume186
Issue number11
Early online date21 Sep 2016
DOIs
Publication statusPublished - 1 Nov 2016

Fingerprint Dive into the research topics of 'Death Receptor 3 promotes chemokine directed leukocyte recruitment in acute resolving inflammation and is essential for pathological development of mesothelial fibrosis in chronic disease'. Together they form a unique fingerprint.

  • Cite this