The Herbert Lab
at UPENN Upenn shield

menu

QUICK ACCESS expand_more

Interleukin 33

Ever since we demonstrated that TFF2 was an early damage-induced molecule that facilitated IL-33 expression, we have become increasingly interested in this peculiar IL-1 family cytokine22. Indeed, there has been an explosion of interest in IL-33 recently given its role in allergic disease and host protection against helminths, but over the past 5-7 years it has become evident that IL-33 is involved in a much wider array of immune responses and diverse biological processes including tissue repair, stem cell function, neural development, and thermoregulation23-25. Perhaps one of the most interesting aspects of its biology is that it is a cytokine constitutively tethered in the nucleus, thought to be released only upon necrotic cell death to function as an alarmin that initiates inflammation26. However, it is now clear that IL-33 also has profound immunoregulatory effects through enhancing the immunosuppressive functions of T regulatory cells (Treg). Whether IL-33 could be delivered from the cell in a manner independent of cell death and whether myeloid lineage cells served as biologically relevant sources of IL-33 have been outstanding questions that many investigators have sought to answer.

It was known that IL-33 could drive expansion of both pro-inflammatory group 2 innate lymphoid cells (ILC2) and immunoregulatory/suppressive Foxp3+ Tregs. Given that our TFF2 studies and studies from others have indicated that both myeloid and epithelial cell lineages could be important sources of IL-3311,27, we formed a hypothesis that cell source could define the biological role for this cytokine. Our recent work demonstrates that indeed, the cellular source of IL-33 can have a radical impact on its biological function: whereas mice lacking intestinal epithelial cell (IEC)-derived IL-33 have impaired Type 2 cytokine production, reduced ILC2 responses, and defects in host resistance to GI nematode infection, mice lacking myeloid APC-derived IL-33 show defects in GATA3+ST2+Foxp3+ Treg numbers and augmented resistance to GI nematodes28.

Moreover, due to the lack of signal peptide, it has remained a puzzle whether IL-33 could be released through a specific mechanism. While cytokines alone can influence lymphocyte lineage decisions and activation status, it is clear that naive T cell priming requires simultaneous delivery of peptide: MHC signals, co-stimulation, and cytokines. Thus it, was reasonable to speculate that cytokines release during cell necrosis would influence T cell function differently from cytokine release from a myeloid APC during synapse formation with a T lymphocyte. Our recently published work demonstrated that the pore-forming protein Perforin-2 is expressed by conventional dendritic cells (cDC) expressing cytoplasmic IL-33 protein, and that the release of IL-33 from cDC was Perforin-2-dependent28. While we do not yet possess direct evidence that Perforin-2 localizes to the immunological synapse, our data revealed that Perforin-2 localizes to the APC-T cell interface during Foxp3+ Treg engagement and that blocking Perforin-2 activity inhibits proliferative expansion of GATA3+ ST2+Foxp3+ Tregs28. We interpret this data that a specific release mechanism exists and this topic is a very active area of research in the lab.

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).

expand_less