Under normal circumstances, mucosal tissue damage caused by abrasions, chemicals, or biological agents is quickly resolved, lest persistent inflammatory responses drive chronic disease. However, the basic understanding of the immunoregulatory and regenerative mechanisms operating at the mucosal interface remains fragmented and unclear. The central goal of this UO1 project is to uncover how Trefoil factor family (TFF) proteins protect the gastrointestinal (GI) tract from injurious inflammatory responses and drive host protection against metazoan parasites and pathogenic bacteria. Preliminary data shows that we have discovered a previously unknown class of receptors for TFF2 and TFF3, a finding that stands to radically impact the cellular and molecular understanding of how Trefoil factor responsiveness in immune cells could govern the balance between tolerance and inflammation. Indeed, we demonstrate that therapeutic administration of TFF3 resolves colitic inflammation and that TFF3 exposure promotes interleukin 10 family cytokine secretion from both human and mouse immune cells. Taken together, the over-arching goal of this project is to bring forth a conceptual and technological advance to the field of Trefoil factor biology. Our two main questions are: (1) whether Trefoil factors function through cognate receptor-ligand interactions with members of the Leucine rich repeat and Ig domain containing, Nogo receptor interacting protein (LINGO) family and (2) whether Trefoil factors critically influence mucosal immune responses in the context of colitis or pathogen infection through regulation of interleukin 10 family cytokine production. Our central hypothesis is that Trefoil factor 3 regulates mucosal IL-10 and IL-22 production through LINGO receptor-dependent mechanisms. Experiments in specific aim 1 will establish whether TFF3 suppresses colitis via LINGO2 and/or LINGO3-dependent mechanisms, those in specific aim 2 will define the pathway(s) and biological importance for TFF3-dependent IL-10 production and experiments in specific aim 3 will define the cellular and molecular mechanism(s) for TFF3-mediated regulation of IL-22. Through successful completion of our project goals, we intend to stimulate broad interest and collaborative investigation of Trefoil factors as an important part of the mechanisms that shape immunity, inflammation, and repair at the mucosal interface.
This U01 project investigates the fundamental role served by Trefoil factor (TFF) proteins in the regulation of immunity at the mucosal interface. We present evidence for a completely new receptor family for TFF proteins and also describe novel regulatory functions for TFF members in suppressing colitic inflammation and driving pathogen clearance from the intestine. Combined, our discovery of a previously unrecognized TFF receptor class and demonstration that TFF's have a strong impact upon the immune system provide much needed information regarding the cellular and molecular mechanisms that control the mucosal surface.
|Patel, Neil N; Kohanski, Michael A; Maina, Ivy W et al. (2018) Solitary chemosensory cells producing interleukin-25 and group-2 innate lymphoid cells are enriched in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol :|
|Hung, Li-Yin; Oniskey, Taylor K; Sen, Debasish et al. (2018) Trefoil Factor 2 Promotes Type 2 Immunity and Lung Repair through Intrinsic Roles in Hematopoietic and Nonhematopoietic Cells. Am J Pathol 188:1161-1170|
|Stoltzfus, Jonathan D; Pilgrim, Adeiye A; Herbert, De'Broski R (2017) Perusal of parasitic nematode 'omics in the post-genomic era. Mol Biochem Parasitol 215:11-22|