Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. IBD afflicts nearly 1.5 million people in the United States. The exact causes of IBD are unknown, but they are thought to generally involve dysregulated host immune responses to commensal microorganisms in genetically susceptible individuals. Tumor necrosis factor (TNF), a major immune cytokine, has a central role in the disease process. While anti-TNF therapies are a part of the medical regimen for many IBD patients, there is mounting evidence that the complete blockade of TNF signaling is not appropriate in the long-term for many. For example, most patients treated with anti-TNF biologics stop responding to the therapy within 5 years. We and others have demonstrated that TNF signaling through its lesser-characterized receptor TNFR2 has many beneficial functions on the repair of the colonic epithelial barrier, a crucial mitigating aspect of IBD, and on the regulation of immune cells including cytotoxic (CD8+) T lymphocytes and regulatory T cells. This application will follow-up on these novel observations to explore the mechanisms that underlie TNFR2's protective effects on CD8+ T cells and colonic epithelial stem cell populations in the setting of colonic injury and inflammation. Specifically, we will: 1) determine the mechanisms by which TNFR2 regulates the pathogenicity of CD8+ T cells in colitis, 2) elucidate the role of TNFR2 in regulation of CD8+ T cell subpopulations and their colonic localization, and 3) define the role of epithelial TNFR2 on colonic epithelial stem cell dynamics and mucosal healing. These studies will reveal important cellular and molecular patterns that may underlie the pathophysiology of IBD.
An understanding of TNFR2's functions in cytotoxic T cells and colonic epithelial cells will promote the argument that specific TNFR2-activating agents can be used to treat IBD. Highlighting the cellular and molecular pathways regulated by TNFR2 will also help identify IBD patients whose specific genetic or physiological profile makes them key candidates for TNFR2-activating treatments.
|Dubé, Philip E; Liu, Cambrian Y; Girish, Nandini et al. (2018) Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 8:9119|
|Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328|
|Miguel, Jennifer C; Maxwell, Adrienne A; Hsieh, Jonathan J et al. (2017) Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci 130:90-96|
|Yan, F; Liu, L; Cao, H et al. (2017) Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood. Mucosal Immunol 10:117-127|
|Wang, Y; Liu, L; Moore, D J et al. (2017) An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells. Mucosal Immunol 10:373-384|
|Zhao, Gang; Liu, Liping; Peek Jr, Richard M et al. (2016) Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. J Biol Chem 291:20462-72|
|Li, Ran; Zhang, Yufeng; Polk, D Brent et al. (2016) Preserving viability of Lactobacillus rhamnosus GG in vitro and in vivo by a new encapsulation system. J Control Release 230:79-87|
|Liu, Cambrian Y; Dubé, Philip E; Girish, Nandini et al. (2015) Optical reconstruction of murine colorectal mucosa at cellular resolution. Am J Physiol Gastrointest Liver Physiol 308:G721-35|
|Dubé, Philip E; Punit, Shivesh; Polk, D Brent (2015) Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 308:G161-70|
|Punit, Shivesh; Dubé, Philip E; Liu, Cambrian Y et al. (2015) Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis. Gastroenterology 149:993-1005.e2|
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