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M2 Macrophages

Early in my scientific career, it dawned on me that evolutionary pressure on the host to deal with damage to skin and mucus membranes caused by helminth parasites would drive the resultant tissue repair processes to adopt immunoregulatory function(s). Work during my postdoctoral days revealed that Type 2 cytokines like interleukin 4 were essential for an "alternative" form of macrophage activation (now termed M2 macrophage) that was essential for survival during infection with the trematode blood fluke Schistosoma mansoni. Schistosoma spp. infect over 250 million people across the globe. During infection, the parasite eggs cause tissue injury resulting in chronic fibrosis, particularly in the liver and lung. However, S. mansoni adult worms residing in the portal vein have evolved to pass their eggs in the stool, which results in moderate intestinal inflammation that is rarely lethal for the host. Our work demonstrated that M2 macrophages were critical for limiting egg-induced inflammation, inasmuch as mice lacking M2 macrophages developed hemorrhagic foci around intestinal eggs and a sepsis-like syndrome that was prevented by administration of broad-spectrum antibiotics1. One implication of this work was that M2 macrophages kept microbial-driven inflammation in check thereby ensuring host survival. That study led to a number of other studies designed to understand the cytokine signals that instructed M2 activation2-4 and the molecules used by tissue macrophages to contain otherwise lethal inflammation in the liver and bowel during worm infection5,6. I became intensely interested in immunoregulatory cytokines like Interleukin 10 and Transforming Growth Factor Beta (TGF-B), and macrophage-derived products like arginase7. This interest broadened to mechanisms responsible for controlling inflammatory bowel diseases7. Studies that focused on mechanisms controlling inflammatory bowel disease were led by Nicole Maloney Belle, MD/PhD, a gastroenterologist and Instructor in the Department of Medicine.

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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