- Review Article
- Published:
Targeting immune cell circuits and trafficking in inflammatory bowel disease
Nature Immunologyvolume 20, pages970–979 (2019)Cite this article
27kAccesses
41Altmetric
Abstract
Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. A defective gut barrier and microbial dysbiosis induce such accumulation and local activation of immune cells, which results in a pro-inflammatory cytokine loop that overrides anti-inflammatory signals and causes chronic intestinal inflammation. This Review discusses pathogenic cytokine responses of immune cells as well as immune cell trafficking as a rational basis for new translational therapies in IBD.
This is a preview of subscription content,access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
9,800 Yen / 30 days
cancel any time
Subscription info for Japanese customers
We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet390, 2769–2778 (2018).
Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease.J. Clin. Invest.117, 514–521 (2007).
Yilmaz, B. et al. Microbial network disturbances in relapsing refractory Crohn’s disease.Nat. Med.25, 323–336 (2019).
Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.Lancet387, 156–167 (2016).
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature491, 119–124 (2012).
Parkes, M. The genetics universe of Crohn’s disease and ulcerative colitis.Dig. Dis.30, 78–81 (2012).
Kiesslich, R. et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease.Gut61, 1146–1153 (2012).
Chang, S. Y. et al. Circulatory antigen processing by mucosal dendritic cells controls CD8+ T cell activation.Immunity38, 153–165 (2013).
Podolsky, D. K. et al. Attenuation of colitis in the cotton-top tamarin by anti-α4 integrin monoclonal antibody.J. Clin. Invest.92, 372–380 (1993).
Sugiura, T. et al. Oral treatment with a novel small molecule α4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice.J. Crohn’s Colitis7, e533–e542 (2013).
Ghosh, S. et al. Natalizumab for active Crohn’s disease.N. Engl. J. Med.348, 24–32 (2003).
Sandborn, W. J. et al. Natalizumab induction and maintenance therapy for Crohn’s disease.N. Engl. J. Med.353, 1912–1925 (2005).
Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease.N. Engl. J. Med.353, 362–368 (2005).
Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis.N. Engl. J. Med.369, 699–710 (2013).
Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease.N. Engl. J. Med.369, 711–721 (2013).
Sandborn, W. J. et al. Efficacy and safety of abrilumab in a randomized, placebo-controlled trial for moderate-to-severe ulcerative colitis.Gastroenterology156, 946–957.e918 (2019).
Wyant, T., Yang, L. & Fedyk, E. In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes.MAbs5, 842–850 (2013).
Zundler, S. et al. Three-dimensional cross-sectional light-sheet microscopy imaging of the inflamed mouse gut.Gastroenterology153, 898–900 (2017).
Uzzan, M. et al. Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals.Sci. Transl. Med.10, eaau4711 (2018).
Kim, M. H., Taparowsky, E. J. & Kim, C. H. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut.Immunity43, 107–119 (2015).
Schleier, L. et al. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing.Guthttps://doi.org/10.1136/gutjnl-2018-316772 (2019).
Vermeire, S. et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial.Lancet390, 135–144 (2017).
Sandborn, W. J. et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn’s disease: report of the OPERA study.Gut67, 1824–1835 (2018).
van Deventer, S. J., Tami, J. A. & Wedel, M. K. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis.Gut53, 1646–1651 (2004).
Greuter, T., Biedermann, L., Rogler, G., Sauter, B. & Seibold, F. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: A case series.United European Gastroenterol. J.4, 97–104 (2016).
Feagan, B. G. et al. Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn’s disease.Aliment. Pharmacol. Ther.42, 1170–1181 (2015).
Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial.Lancet384, 309–318 (2014).
Agace, W. W., Higgins, J. M., Sadasivan, B., Brenner, M. B. & Parker, C. M. T-lymphocyte-epithelial-cell interactions: integrin αE(CD103)β7, LEEP-CAM and chemokines.Curr. Opin. Cell Biol.12, 563–568 (2000).
Lamb, C. A. et al. αEβ7 integrin identifies subsets of pro-inflammatory colonic CD4+ T lymphocytes in ulcerative colitis.J. Crohn’s Colitis11, 610–620 (2017).
Zundler, S. et al. Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo.Gut11, 1936–1948 (2016).
Zundler, S. et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation.Nat. Immunol.20, 288–300 (2019).
Bishu, S. et al. CD4+ tissue-resident memory T cells expand and are a major source of mucosal tumour necrosis factor α in active Crohn’s disease.J. Crohn’s Colitishttps://doi.org/10.1093/ecco-jcc/jjz010 (2019).
Sandborn, W. J. et al. Ozanimod induction and maintenance treatment for ulcerative colitis.N. Engl. J. Med.374, 1754–1762 (2016).
West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.Nat. Med.23, 579–589 (2017).
Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.Nature464, 1371–1375 (2010).
Neurath, M. F., Fuss, I., Kelsall, B. L., Stüber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice.J. Exp. Med.182, 1281–1290 (1995).
Gerlach, K. et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells.Nat. Immunol.15, 676–686 (2014).
Monteleone, G. et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells.Gastroenterology112, 1169–1178 (1997).
Kotlarz, D. et al. Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy.Nat. Genet.50, 344–348 (2018).
Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.N. Engl. J. Med.361, 2033–2045 (2009).
Kotlarz, D. et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.Gastroenterology143, 347–355 (2012).
Caudy, A. A., Reddy, S. T., Chatila, T., Atkinson, J. P. & Verbsky, J. W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.J. Allergy Clin. Immunol.119, 482–487 (2007).
Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.J. Clin. Invest.116, 1310–1316 (2006).
Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology.Immunity25, 309–318 (2006).
Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis.J. Clin. Invest.118, 534–544 (2008).
Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.Immunity1, 553–562 (1994).
Colombel, J. F. et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease.N. Engl. J. Med.362, 1383–1395 (2010).
Panaccione, R. et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.Gastroenterology146, 392–400.e3 (2014).
Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for crohn’s disease.N. Engl. J. Med.375, 1946–1960 (2016).
Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease.N. Engl. J. Med.367, 1519–1528 (2012).
Danese, S. et al. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study.Gut64, 243–249 (2015).
Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial.Gut61, 1693–1700 (2012).
Reinisch, W. et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease.Gut55, 1138–1144 (2006).
Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II).Gut68, 40–48 (2019).
Wirtz, S., Becker, C., Blumberg, R., Galle, P. R. & Neurath, M. F. Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA.J. Immunol.168, 411–420 (2002).
Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity.Immunity50, 778–795 (2019).
Casini-Raggi, V. et al. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation.J. Immunol.154, 2434–2440 (1995).
Shouval, D. S. et al. Interleukin 1β mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency.Gastroenterology151, 1100–1104 (2016).
Coccia, M. et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells.J. Exp. Med.209, 1595–1609 (2012).
Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer.Immunity50, 166–180.e167 (2019).
Cominelli, F. et al. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis.J. Clin. Invest.86, 972–980 (1990).
Bauer, C. et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.Gut59, 1192–1199 (2010).
Castro-Dopico, T. et al. Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis.Immunity50, 1099–1114.e10 (2019).
Siegmund, B., Lehr, H. A., Fantuzzi, G. & Dinarello, C. A. IL-1β-converting enzyme (caspase-1) in intestinal inflammation.Proc. Natl Acad. Sci. USA98, 13249–13254 (2001).
Neudecker, V. et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome.J. Exp. Med.214, 1737–1752 (2017).
Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis.Cell163, 1444–1456 (2015).
Ten Hove, T. et al. Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-α production in mice.Gastroenterology121, 1372–1379 (2001).
Kanai, T. et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease.Gastroenterology121, 875–888 (2001).
Pizarro, T. T. et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells.J. Immunol.162, 6829–6835 (1999).
Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis.Proc. Natl Acad. Sci. USA107, 8017–8022 (2010).
Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity.Proc. Natl Acad. Sci. USA107, 18581–18586 (2010).
He, Z. et al. Mast cells are essential intermediaries in regulating IL-33/ST2 signaling for an immune network favorable to mucosal healing in experimentally inflamed colons.Cell Death Dis.9, 1173 (2018).
Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine.Nature513, 564–568 (2014).
Russell, S. E. et al. IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation.Mucosal Immunol.9, 1193–1204 (2016).
Scheibe, K. et al. IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo.Gut66, 823–838 (2017).
Medina-Contreras, O. et al. Cutting edge: IL-36 receptor promotes resolution of intestinal damage.J. Immunol.196, 34–38 (2016).
Ngo, V. L. et al. A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.Proc. Natl Acad. Sci. USA115, E5076–E5085 (2018).
Scheibe, K. et al. Inhibiting Interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology156, 1082–1097.e1011 (2019).
Imaeda, H. et al. Epithelial expression of interleukin-37b in inflammatory bowel disease.Clin. Exp. Immunol.172, 410–416 (2013).
McNamee, E. N. et al. Interleukin 37 expression protects mice from colitis.Proc. Natl Acad. Sci. USA108, 16711–16716 (2011).
Wang, W. Q. et al. IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice.Acta Pharmacol. Sin.36, 1377–1387 (2015).
Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo.Nat. Med.6, 583–588 (2000).
Atreya, R. & Neurath, M. F. Signaling molecules: the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer.Curr. Drug Targets9, 369–374 (2008).
Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer.Cancer Cell15, 103–113 (2009).
Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.Immunity21, 491–501 (2004).
Ito, H. et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease.Gastroenterology126, 989–996 (2004). discussion 947.
Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.Nature477, 335–339 (2011).
Atreya, R. et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages.Gastroenterology141, 2026–2038 (2011).
Atreya, R. et al. In vivo molecular imaging using fluorescent anti-TNF antibodies predicts response to biological therapy in Crohn’s disease.Nat. Med.52, 313–318 (2014).
Perrier, C. et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis.Inflamm. Bowel Dis.19, 246–253 (2013).
Hanauer, S. B. et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial.Lancet359, 1541–1549 (2002).
Ordás, I., Feagan, B. G. & Sandborn, W. J. Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change.Gut60, 1754–1763 (2011).
Heller, F. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution.Gastroenterology129, 550–564 (2005).
Fuss, I. J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5.J. Immunol.157, 1261–1270 (1996).
Nalleweg, N. et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC.Gut64, 743–755 (2015).
Kobayashi, T. et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease.Gut57, 1682–1689 (2008).
Kvedaraite, E. et al. Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD.Gut65, 1632–1641 (2016).
Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease.J. Exp. Med.195, 1129–1143 (2002).
Leppkes, M. et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.Gastroenterology136, 257–267 (2009).
Aden, K. et al. Epithelial IL-23R signaling licenses protective IL-22 responses in intestinal inflammation.Cell Reports16, 2208–2218 (2016).
Cox, J. H. et al. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice.Mucosal Immunol.5, 99–109 (2012).
Maxwell, J. R. et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation.Immunity43, 739–750 (2015).
Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability.Immunity43, 727–738 (2015).
Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study.Gastroenterology153, 77–86.e76 (2017).
Feagan, B. G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study.Lancet389, 1699–1709 (2017).
Danne, C. et al. A large polysaccharide produced byHelicobacter hepaticus induces an anti-inflammatory gene signature in macrophages.Cell Host Microbe22, 733–745.e735 (2017).
Brockmann, L. et al. Molecular and functional heterogeneity of IL-10-producing CD4+ T cells.Nat. Commun.9, 5457 (2018).
Kühn, R., Löhler, J., Rennick, D., Rajewsky, K. & Müller, W. Interleukin-10-deficient mice develop chronic enterocolitis.Cell75, 263–274 (1993).
Uhlig, H. H. et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis.J. Immunol.177, 5852–5860 (2006).
Zigmond, E. et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis.Immunity40, 720–733 (2014).
Neumann, C. et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis.Nat. Immunol.20, 471–481 (2019).
Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils.Immunity10, 39–49 (1999).
Steidler, L. et al. Treatment of murine colitis byLactococcus lactis secreting interleukin-10.Science289, 1352–1355 (2000).
Braat, H., Peppelenbosch, M. P. & Hommes, D. W. Interleukin-10-based therapy for inflammatory bowel disease.Expert Opin. Biol. Ther.3, 725–731 (2003).
Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease.Clin. Gastroenterol. Hepatol.4, 754–759 (2006).
Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells.J. Exp. Med.183, 2669–2674 (1996).
Fantini, M. C. et al. Transforming growth factor β induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis.Gut55, 671–680 (2006).
Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease.N. Engl. J. Med.372, 1104–1113 (2015).
Feagan, B. G. et al. Effects of mongersen (GED-0301) on endoscopic and clinical outcomes in patients with active Crohn’s disease.Gastroenterology154, 61–64.e66 (2018).
Spangler, J. B. et al. Antibodies to interleukin-2 elicit selective t cell subset potentiation through distinct conformational mechanisms.Immunity42, 815–825 (2015).
Silva, D. A. et al. De novo design of potent and selective mimics of IL-2 and IL-15.Nature565, 186–191 (2019).
Atreya, R. et al. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis.Dig. Liver Dis.50, 1019–1029 (2018).
Voskens, C. J. et al. Characterization and expansion of autologous GMP-ready regulatory T cells for TREG-based cell therapy in patients with ulcerative colitis.Inflamm. Bowel Dis.23, 1348–1359 (2017).
Desreumaux, P. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease.Gastroenterology143, 1207–1217 (2012).
Leung, J.M. et al. IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue.Mucosal Immunol.7, 124–133 (2014).
Pelczar, P. et al. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease.Science354, 358–362 (2016).
Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing.J. Exp. Med.206, 1465–1472 (2009).
Aden, K. et al. ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.J. Exp. Med.215, 2868–2886 (2018).
Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.Nature491, 259–263 (2012).
Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract.Gastroenterology141, 237–248.e231 (2011).
Naganuma, M. et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis.Gastroenterology154, 935–947 (2018).
Chiriac, M. T. et al. Activation of epithelial signal transducer and activator of transcription 1 by interleukin 28 controls mucosal healing in mice with colitis and is increased in mucosa of patients with inflammatory bowel disease.Gastroenterology153, 123–138.e8 (2017).
Biancheri, P. et al. Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease.Gastroenterology149, 1564–1574.e3 (2015).
Atreya, R. & Neurath, M. F. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease.Gastroenterol. Hepatol.3, 790–802 (2018).
Belarif, L. et al. IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.J. Clin. Invest.130, 1910–1925 (2019).
Schmitt, H. et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease.Gut68, 814–828 (2019).
Sandborn, W. J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis.N. Engl. J. Med.367, 616–624 (2012).
Vermeire, S. et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.Lancet389, 266–275 (2017).
Popp, V. et al. Rectal delivery of a DNAzyme that specifically blocks the transcription factor GATA3 reduces colitis in mice.Gastroenterology152, 176–192 (2017).
Withers, D. R. et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.Nat. Med.22, 319–323 (2016).
Colombel, J. F. et al. Adalimumab safety in global clinical trials of patients with Crohn’s disease.Inflamm. Bowel Dis.15, 1308–1319 (2009).
Zundler, S. et al. The α4β1 homing pathway is essential for ileal homing of Crohn’s disease effector T cells in vivo.Inflamm. Bowel Dis.23, 379–391 (2017).
Tillack, C. et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment.Gut63, 567–577 (2014).
Hanson, M. L. et al. Oral Delivery of IL-27 recombinant bacteria attenuates immune colitis in mice.Gastroenterology146, 210–221.e213 (2014).
Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages.Immunity50, 432–445 e437 (2019).
Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.Lancet389, 1218–1228 (2017).
Neurath, M. F. Cytokines in inflammatory bowel disease.Nat. Rev. Immunol.14, 329–342 (2014).
Acknowledgements
The research of M.F.N. was funded by the DFG (SFB1181, TRR241, FOR2438, SAOT graduate school), by the Interdisciplinary Centre for Clinical Research Erlangen and by the FAU Emerging Fields Initiative.
Author information
Authors and Affiliations
Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Deutsches Zentrum Immuntherapie DZI, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
Markus F. Neurath
- Markus F. Neurath
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toMarkus F. Neurath.
Ethics declarations
Competing interests
M.F.N. has served as an advisor to Pentax, PPD, Abbvie, Boehringer, MSD, Janssen, Roche, Genentech, Shire and Takeda. M.F.N. received research support from Takeda, Boehringer, Roche and Shire.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Neurath, M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease.Nat Immunol20, 970–979 (2019). https://doi.org/10.1038/s41590-019-0415-0
Received:
Accepted:
Published:
Issue Date:
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
