Death Receptor 3 Promotes Chemokine-Directed Leukocyte Recruitment in Acute Resolving Inflammation and Is Essential for Pathological Development of Mesothelial Fibrosis in Chronic Disease.
Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factor-like 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 (DR3+/+) 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 DR3+/+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.
Department of Medical Microbiology and Infectious Disease, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
William V
WV
Perks
Department of Medical Microbiology and Infectious Disease, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Ravinder K
RK
Singh
Department of Rheumatology, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Gareth W
GW
Jones
Department of Medical Microbiology and Infectious Disease, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom; Department of Rheumatology, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Jason P
JP
Twohig
Department of Rheumatology, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Anwen S
AS
Williams
Department of Medical Microbiology and Infectious Disease, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Ian R
IR
Humphreys
Department of Rheumatology, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Philip R
PR
Taylor
Department of Rheumatology, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Simon A
SA
Jones
Department of Medical Microbiology and Infectious Disease, Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom. Electronic address: wangec@cf.ac.uk.
Eddie C Y
ECY
Wang
D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D004848:Epithelium / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000502:physiology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013212:Staphylococcus epidermidis / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
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