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Trefoil Factor Proteins

Upon establishing my own laboratory, I decided to focus on understanding the mechanisms that governed immunity during the earliest steps in the host-parasite interaction. This led to a keen interest in mucosal epithelial cells and the processes regulating wound healing at the mucosal interface. It was at this point that I came across the Trefoil Factor Family (TFF) proteins—small reparative proteins highly expressed at mucosal surfaces, but whose role in immunity was then unknown8-10. The decision to turn my focus to TFF proteins was risky yet exhilarating, and ultimately extremely rewarding. Through collaborative studies with Dr. Marsha Wills Karp and others, we found that TFF2 was upregulated in pediatric asthma patients and in mice experiencing allergic airway disease or hookworm infection11. Unexpectedly, we found that TFF2 functioned to promote expression of IL 33, a cytokine that had gained considerable attention from GWAS studies implicating it in human asthma12-14. Additionally, we found that TFF2 served an antagonistic role for Type 1 inflammatory responses against protozoan parasite infections15. Although originally thought to be solely an epithelial cell-derived product, we now know that myeloid antigen-presenting cells (APCs) can serve as a critical source of TFF2, driving tissue repair by inducing proliferative expansion of nascent epithelial cells following airway damage caused by parasites or chemical injury16.

However, by far the greatest barrier to scientific progress in the field of TFF biology was the lack of a bona fide TFF receptor(s)8. It was clear that TFFs could induce conventional signaling cascades involving MAPK and EGFR signaling to mediate their reparative functions, which implied receptor-ligand interations, but this was highly debated. Using a variety of biochemical and molecular approaches, we identified leucine rich repeat nogo interacting protein 2 (LINGO2) as a Type I transmembrane receptor for TFF317. Our data demonstrated that LINGO2 functioned as a negative regulator of epidermal growth factor receptor (EGFR) signaling and that TFF3 facilitated activation of EGFR by sequestering LINGO2 away from EGFR, thus acting as a rheostat to govern the extent of EGFR activity17. This provided a conceptual framework for potentially explaining how TFF3 could drive mucosal wound healing through EGFR activation. These studies have opened the door for investigating the role of LINGO receptors in mucosal wound healing, which was completely unexplored prior to our investigations. Upon moving my lab to UPenn, we started collaborating extensively with Noam Cohen MD/PhD (UPenn) and Andrew Vaughan (PennVet) to further investigate how epithelial cell populations in the upper and lower airway respond to the injurious effects of allergen exposure and viral infection19-21.

References

  1. Herbert, D. R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623-635, doi:10.1016/s1074-7613(04)00107-4 (2004).

  2. Rani, R., Jordan, M. B., Divanovic, S. & Herbert, D. R. IFN-gamma-driven IDO production from macrophages protects IL-4Ralpha-deficient mice against lethality during Schistosoma mansoni infection. Am J Pathol 180, 2001-2008, doi:10.1016/j.ajpath.2012.01.013 (2012).

  3. Fontana, M. F. et al. Myeloid expression of the AP-1 transcription factor JUNB modulates outcomes of type 1 and type 2 parasitic infections. Parasite Immunol 37, 470-478, doi:10.1111/pim.12215 (2015).

  4. Fontana, M. F. et al. JUNB is a key transcriptional modulator of macrophage activation. J Immunol 194, 177-186, doi:10.4049/jimmunol.1401595 (2015).

  5. Herbert, D. R. et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol 184, 6438-6446, doi:10.4049/jimmunol.0902009 (2010).

  6. Herbert, D. R., Orekov, T., Perkins, C. & Finkelman, F. D. IL-10 and TGF-beta redundantly protect against severe liver injury and mortality during acute schistosomiasis. J Immunol 181, 7214-7220, doi:10.4049/jimmunol.181.10.7214 (2008).

  7. Rani, R., Smulian, A. G., Greaves, D. R., Hogan, S. P. & Herbert, D. R. TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol 41, 2000-2009, doi:10.1002/eji.201041135 (2011).

  8. Taupin, D. & Podolsky, D. K. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4, 721-732, doi:10.1038/nrm1203 (2003).

  9. Kinoshita, K., Taupin, D. R., Itoh, H. & Podolsky, D. K. Distinct pathways of cell migration and antiapoptotic response to epithelial injury: structure-function analysis of human intestinal trefoil factor. Mol Cell Biol 20, 4680-4690, doi:10.1128/MCB.20.13.4680-4690.2000 (2000).

  10. Taupin, D. R., Kinoshita, K. & Podolsky, D. K. Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Proc Natl Acad Sci U S A 97, 799-804, doi:10.1073/pnas.97.2.799 (2000).

  11. Wills-Karp, M. et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 209, 607-622, doi:10.1084/jem.20110079 (2012).

  12. Savenije, O. E. et al. Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. J Allergy Clin Immunol 134, 170-177, doi:10.1016/j.jaci.2013.12.1080 (2014).

  13. Bonnelykke, K. et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 46, 51-55, doi:10.1038/ng.2830 (2014).

  14. Ho, J. E. et al. Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J Clin Invest 123, 4208-4218, doi:10.1172/JCI67119 (2013).

  15. McBerry, C. et al. Trefoil factor 2 negatively regulates type 1 immunity against Toxoplasma gondii. J Immunol 189, 3078-3084, doi:10.4049/jimmunol.1103374 (2012).

  16. Hung, L. Y. et al. Trefoil Factor 2 Promotes Type 2 Immunity and Lung Repair through Intrinsic Roles in Hematopoietic and Nonhematopoietic Cells. Am J Pathol 188, 1161-1170, doi:10.1016/j.ajpath.2018.01.020 (2018).

  17. Belle, N. M. et al. TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths. Nat Commun 10, 4408, doi:10.1038/s41467-019-12315-1 (2019).

  18. Zullo, K. M. et al. LINGO3 regulates mucosal tissue regeneration and promotes TFF2 dependent recovery from colitis. Scand J Gastroenterol 56, 791-805, doi:10.1080/00365521.2021.1917650 (2021).

  19. Patel, N. N. et al. Sentinels at the wall: epithelial-derived cytokines serve as triggers of upper airway type 2 inflammation. Int Forum Allergy Rhinol 9, 93-99, doi:10.1002/alr.22206 (2019).

  20. Patel, N. N. et al. Fungal extracts stimulate solitary chemosensory cell expansion in noninvasive fungal rhinosinusitis. Int Forum Allergy Rhinol 9, 730-737, doi:10.1002/alr.22334 (2019).

  21. Rane, C. K. et al. Development of solitary chemosensory cells in the distal lung after severe influenza injury. Am J Physiol Lung Cell Mol Physiol 316, L1141-L1149, doi:10.1152/ajplung.00032.2019 (2019).

  22. Hung, L. Y., Pastore, C. F., Douglas, B. & Herbert, D. R. Myeloid-Derived IL-33 Limits the Severity of Dextran Sulfate Sodium-Induced Colitis. Am J Pathol 191, 266-273, doi:10.1016/j.ajpath.2020.11.004 (2021).

  23. Vainchtein, I. D. et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359, 1269-1273, doi:10.1126/science.aal3589 (2018).

  24. Odegaard, J. I. et al. Perinatal Licensing of Thermogenesis by IL-33 and ST2. Cell 166, 841-854, doi:10.1016/j.cell.2016.06.040 (2016).

  25. Mahapatro, M. et al. Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection. Cell Rep 15, 1743-1756, doi:10.1016/j.celrep.2016.04.049 (2016).

  26. Cayrol, C. & Girard, J. P. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol Rev 281, 154-168, doi:10.1111/imr.12619 (2018).

  27. Hsu, C. L., Neilsen, C. V. & Bryce, P. J. IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS One 5, e11944, doi:10.1371/journal.pone.0011944 (2010).

  28. Hung, L. Y. et al. Cellular context of IL-33 expression dictates impact on anti-helminth immunity. Sci Immunol 5, doi:10.1126/sciimmunol.abc6259 (2020).

  29. Lok, J. B. CRISPR/Cas9 Mutagenesis and Expression of Dominant Mutant Transgenes as Functional Genomic Approaches in Parasitic Nematodes. Front Genet 10, 656, doi:10.3389/fgene.2019.00656 (2019).

  30. Douglas, B. et al. Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations. PLoS Pathog 17, e1009709, doi:10.1371/journal.ppat.1009709 (2021).

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