The Tumor Necrosis Factor Superfamily Members TNFSF14 (LIGHT), Lymphotoxin β and Lymphotoxin β Receptor Interact to Regulate Intestinal Inflammation
| Autor: | Venetia Morris, Alexei V. Tumanov, Daniel A. Giles, Esmé T I van der Gracht, Petra Krause, Sonja Zahner, Mitchell Kronenberg, Thomas Riffelmacher |
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| Rok vydání: | 2018 |
| Předmět: |
Lymphotoxin-beta
lcsh:Immunologic diseases. Allergy 0301 basic medicine Tumor Necrosis Factor Ligand Superfamily Member 14 Light Immunology Inflammation Biology Inflammatory bowel disease Pathogenesis Mice 03 medical and health sciences Lymphotoxin beta Receptor medicine Animals Humans Immunology and Allergy Colitis Receptor Lymphotoxin (LT) Original Research TNF superfamily Mice Knockout Tumor Necrosis Factor-alpha Dextran Sulfate Inflammatory Bowel Diseases medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Lymphotoxin Disease Progression Cancer research Tumor necrosis factor alpha DSS (dextran sulfate sodium) medicine.symptom lcsh:RC581-607 Lymphotoxin beta receptor Signal Transduction |
| Zdroj: | Frontiers in Immunology, Vol 9 (2018) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2018.02585 |
| Popis: | Over 1.5 million individuals in the United States are afflicted with inflammatory bowel disease (IBD). While the progression of IBD is multifactorial, chronic, unresolved inflammation certainly plays a key role. Additionally, while multiple immune mediators have been shown to affect pathogenesis, a comprehensive understanding of disease progression is lacking. Previous work has demonstrated that a member of the TNF superfamily, TNFSF14 (LIGHT), which is pro-inflammatory in several contexts, surprisingly plays an important role in protection from inflammation in mouse models of colitis, with LIGHT deficient mice having more severe disease pathogenesis. However, LIGHT is a single member of a complex signaling network. It signals through multiple receptors, including herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTβR); these two receptors in turn can bind to other ligands. It remains unknown which receptors and competing ligands can mediate or counteract the outcome of LIGHT-signaling during colitis. Here we demonstrate that LIGHT signaling through LTβR, rather than HVEM, plays a critical role in the progression of DSS-induced colitis, as LTβR deficient mice exhibit a more severe disease phenotype. Further, mice deficient in LTαβ do not exhibit differential colitis progression compared to WT mice. However, deletion of both LIGHT and LTαβ, but not deletion of both LTαβ and LTβR, resulted in a reversal of the adverse effects associated with the loss of LIGHT. In sum, the LIGHT/LTαβ/LTβR signaling network contributes to DSS colitis, but there may be additional receptors or indirect effects, and therefore, the relationships between these receptors and ligands remains enigmatic. |
| Databáze: | OpenAIRE |
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