The Tumor Necrosis Factor Superfamily Members TNFSF14 (LIGHT), Lymphotoxin β and Lymphotoxin β Receptor Interact to Regulate Intestinal Inflammation

• Main Authors: Daniel A. Giles, Sonja Zahner, Petra Krause, Esmé Van Der Gracht, Thomas Riffelmacher, Venetia Morris, Alexei Tumanov, Mitchell Kronenberg
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-11-01
• Series: Frontiers in Immunology
• Subjects: TNF superfamily; Colitis; Lymphotoxin (LT); Light; DSS (dextran sulfate sodium)
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2018.02585/full

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.