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Sensory Neurons & Allergies

Our interests in dissecting the critical neuro-immune interactions that control inflammation and homeostasis also extends to understanding allergic disease within the upper airway. This project has grown out of our highly productive collaboration with Noam Cohen, MD/PhD. Noam has a keen interest in chronic rhinosinusitis (CRS), and together we have established a mouse model of sinonasal Type 2 allergic inflammation evoked by a 3-week intranasal administration of Alternaria alternata and Aspergillus fumigatus  fungal allergen mix (FAM) in C57BL/6J mice. This model replicates key features of allergic fungal rhinosinusitis (AFRS), which is a subtype of CRS observed in patients, including the expansion of sinonasal Tuft cells (STC), tissue ILC2, eosinophils, goblet cells, and increased levels of IL-25 and IL-33 in the sinonasal fluid. While we have primarily focused on STC to date, we are continuing to use this model to investigate whether sensory neurons of the sinonasal mucosa that emanate from the trigeminal ganglion (TG) are instrumental in driving Type 2 allergic inflammation. Given that STC are innervated by TG neurons, the latter of which express the transient receptor potential vanilloid 1 (TRPV1+) ion channel, the same mouse models that we are building for investigating the role of skin sensory neurons in host protection against helminths are being used to investigate the role of neuronal inputs in allergic respiratory disease. Specifically, we are testing whether local interactions between STC and neurons in the sinonasal tract are required for development of allergen-induced Type 2 inflammation.

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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