The lymphotoxin beta receptor (LT?R), a member of the TNF super family of receptors (TNFSFR3), binds to two ligands: lymphotoxin beta (LT? or TNFSF3) and LIGHT (TNFSF14). LIGHT binds to another receptor, HVEM (TNFSFR14) and polymorphisms in HVEM are associated with a risk for ulcerative colitis. It is well established that the LT?R is involved in promoting inflammatory responses in several contexts. Surprisingly, however, our data from mouse models of colitis indicate that interaction of the LT?R with LIGHT, but not with LT?, prevents severe inflammation by limiting innate immunity. Our goal therefore is to understand how LIGHT-LT?R contact prevents severe inflammation. We will determine the critical cell types that express this ligand-receptor pair, what types of inflammatory responses are amplified when these cells do not express LIGHT or the LT?R, and how the LIGHT- LT?R interaction affects the intestinal microbiome or its metabolic output. We will accomplish this using two colitis models. One model is induced by chemical injury to the intestine by dextran sodium sulfate (DSS). The transfer of nave CD4+ T cells to immune deficient mice initiates the second model. Using these means to induce colitis, we will analyze carefully the cytokines, chemokines and immune response during the course of inflammation in mice with the gene for the LT?R deleted in key cells that influence innate immunity, such as epithelial cells, macrophages or neutrophils. Similarly, LIGHT will be deleted in target cells, such as neutrophils, dendritic cells and a type of innate lymphoid cell (ILC3) that produces IL-22. Once the important cell type(s) are identified, we will use in vivo and in vitro experiments to determine how engagement of the LT?R affects that cell. Because the normal interaction between the immune system and the intestinal microbiome is disturbed in IBD, we also will determine if the microbiome and its metabolome are altered in mice with cell type-specific deletion of the LT?R or its ligand. Furthermore, by manipulating the microbiome or its metabolic output, we will explore if changes in the microbiome can ameliorate the severe disease that occurs in the absence of LT?R signals. The insights from this research will not only help to understand pathways that lead to intestine inflammation, but they will help to establish if engaging the LT?R with antibody, or with its ligand LIGHT, could be useful for treating some IBD patients with particular biomarkers indicative of these pathways.
Preventing the binding of an immune mediator known as tumor necrosis factor (TNF) from binding to TNF receptors helps some patients with IBD. Using animal models, we e have found that a relative of the TNF receptor, known as the lymphotoxin receptor, has the opposite effect as it limits rather than promoting intestine inflammation. Our experiments are designed to understand precisely how this occurs, meaning what cell type has to express the lymphotoxin receptor and how it prevents severe inflammation, so that this pathway can be targeted effectively to help patients with IBD.
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