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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK046763-24
Application #
9074363
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (J3)P)
Project Start
Project End
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
24
Fiscal Year
2016
Total Cost
$423,006
Indirect Cost
$151,253
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42
Seo, Goo-Young; Shui, Jr-Wen; Takahashi, Daisuke et al. (2018) LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection. Cell Host Microbe 24:249-260.e4
Clerc, Florent; Novokmet, Mislav; Dotz, Viktoria et al. (2018) Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases. Gastroenterology 155:829-843
Rivas, Manuel A; Avila, Brandon E; Koskela, Jukka et al. (2018) Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet 14:e1007329
Hong, Myunghee; Ye, Byong Duk; Yang, Suk-Kyun et al. (2018) Immunochip Meta-Analysis of Inflammatory Bowel Disease Identifies Three Novel Loci and Four Novel Associations in Previously Reported Loci. J Crohns Colitis 12:730-741
Freise, Amanda C; Zettlitz, Kirstin A; Salazar, Felix B et al. (2018) Immuno-PET in Inflammatory Bowel Disease: Imaging CD4-Positive T Cells in a Murine Model of Colitis. J Nucl Med 59:980-985
Šimurina, Mirna; de Haan, Noortje; Vu?kovi?, Frano et al. (2018) Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology 154:1320-1333.e10
Leonardi, Irina; Li, Xin; Semon, Alexa et al. (2018) CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359:232-236
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Schwerd, T; Bryant, R V; Pandey, S et al. (2018) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol 11:562-574

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