Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
Nick Powell, Eirini Pantazi, Polychronis Pavlidis, Anastasia Tsakmaki, Katherine Li, Feifei Yang, Aimee Parker, Carmen Pin, Domenico Cozzetto, Danielle Minns, Emilie Stolarczyk, Svetlana Saveljeva, Rami Mohamed, Paul Lavender, Behdad Afzali, Jonathan Digby-Bell, Tsui Tjir-Li, Arthur Kaser, Joshua Friedman, Thomas T MacDonald, Gavin A Bewick, Graham M Lord, Nick Powell, Eirini Pantazi, Polychronis Pavlidis, Anastasia Tsakmaki, Katherine Li, Feifei Yang, Aimee Parker, Carmen Pin, Domenico Cozzetto, Danielle Minns, Emilie Stolarczyk, Svetlana Saveljeva, Rami Mohamed, Paul Lavender, Behdad Afzali, Jonathan Digby-Bell, Tsui Tjir-Li, Arthur Kaser, Joshua Friedman, Thomas T MacDonald, Gavin A Bewick, Graham M Lord
Abstract
Objective: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.
Design: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.
Results: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.
Conclusions: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.
Trial registration number: NCT02749630.
Keywords: ER stress; Interleukin 22; inflammatory bowel disease.
Conflict of interest statement
Competing interests: None declared.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
Figures
References
- Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med Overseas Ed 2009;361:2066–78.10.1056/NEJMra0804647
- Lindemans CA, Calafiore M, Mertelsmann AM, et al. . Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 2015;528:560–4.10.1038/nature16460
- Sanos SL, Bui VL, Mortha A, et al. . Rorgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 2009;10:83–91.10.1038/ni.1684
- Satoh-Takayama N, Vosshenrich CAJ, Lesjean-Pottier S, et al. . Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 2008;29:958–70.10.1016/j.immuni.2008.11.001
- Koroleva E, Muraoka W, Spencer C, et al. . O-009 Lymphotoxin Links Microbiota and Group 3 Innate Lymphoid Cells to Protect Against Intestinal Inflammation. Inflamm Bowel Dis 2016;22:S3–4.10.1097/01.MIB.0000480047.19127.68
- Sugimoto K, Ogawa A, Mizoguchi E, et al. . Il-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008;118:534–44.10.1172/JCI33194
- Aparicio-Domingo P, Romera-Hernandez M, Karrich JJ, et al. . Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J Exp Med 2015;212:1783–91.10.1084/jem.20150318
- Eken A, Singh AK, Treuting PM, et al. . IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol 2014;7:143–54.10.1038/mi.2013.33
- Kamanaka M, Huber S, Zenewicz LA, et al. . Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med 2011;208:1027–40.10.1084/jem.20102149
- Kirchberger S, Royston DJ, Boulard O, et al. . Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 2013;210:917–31.10.1084/jem.20122308
- Aden K, Tran F, Ito G, et al. . ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J Exp Med 2018;215:2868–86.10.1084/jem.20171029
- Feagan BG, Sandborn WJ, D'Haens 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. Lancet 2017;389:1699–709.10.1016/S0140-6736(17)30570-6
- Sands BE, Chen J, Feagan BG, 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. Gastroenterology 2017;153:77–86.10.1053/j.gastro.2017.03.049
- Garrett WS, Lord GM, Punit S, et al. . Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 2007;131:33–45.10.1016/j.cell.2007.08.017
- Hiramatsu N, Chiang W-C, Kurt TD, et al. . Multiple mechanisms of unfolded protein Response-Induced cell death. Am J Pathol 2015;185:1800–8.10.1016/j.ajpath.2015.03.009
- Akiyama T, Oishi K, Wullaert A. Bifidobacteria prevent tunicamycin-induced endoplasmic reticulum stress and subsequent barrier disruption in human intestinal epithelial Caco-2 monolayers. PLoS One 2016;11:e016244810.1371/journal.pone.0162448
- Subramanian A, Tamayo P, Mootha VK, et al. . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545–50.10.1073/pnas.0506580102
- Pham TAN, Clare S, Goulding D, et al. . Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 2014;16:504–16.10.1016/j.chom.2014.08.017
- Powell N, Lo JW, Biancheri P, et al. . Interleukin 6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology 2015;149:456–67.10.1053/j.gastro.2015.04.017
- Powell N, Walker AW, Stolarczyk E, et al. . The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 2012;37:674–84.10.1016/j.immuni.2012.09.008
- Nakagawa T, Zhu H, Morishima N, et al. . Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000;403:98–103.10.1038/47513
- Shiraishi H, Okamoto H, Yoshimura A, et al. . ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci 2006;119:3958–66.10.1242/jcs.03160
- Wang C, Gong G, Sheh A, et al. . Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer. Mucosal Immunol 2017;10:1504–17.10.1038/mi.2017.9
- Yang L, Calay ES, Fan J, et al. . Metabolism. S-nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 2015;349:500–6.10.1126/science.aaa0079
- Kumar V. A sting to inflammation and autoimmunity. J Leukoc Biol 2019;106:171–85.10.1002/JLB.4MIR1018-397RR
- Thomas PD, Campbell MJ, Kejariwal A, et al. . Panther: a library of protein families and subfamilies indexed by function. Genome Res 2003;13:2129–41.10.1101/gr.772403
- Kanehisa M, Sato Y, Furumichi M, et al. . New approach for understanding genome variations in KEGG. Nucleic Acids Res 2019;47:D590–5.10.1093/nar/gky962
- Garside P, Bunce C, Tomlinson RC, et al. . Analysis of enteropathy induced by tumour necrosis factor alpha. Cytokine 1993;5:24–30.10.1016/1043-4666(93)90020-6
- Piguet PF, Vesin C, Guo J, et al. . Tnf-Induced enterocyte apoptosis in mice is mediated by the TNF receptor 1 and does not require p53. Eur J Immunol 1998;28:3499–505.10.1002/(SICI)1521-4141(199811)28:11<3499::AID-IMMU3499>;2-Q
- Feagan BG, Sandborn WJ, Gasink C, et al. . Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2016;375:1946–60.10.1056/NEJMoa1602773
- Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 2013;14:710.1186/1471-2105-14-7
- Arijs I, Li K, Toedter G, et al. . Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 2009;58:1612–9.10.1136/gut.2009.178665
- Huang S, Hu C, Bell ML, et al. . Regularized continuous-time Markov model via elastic net. Biometrics 2018;74:1045–54.10.1111/biom.12868
- Pickert G, Neufert C, Leppkes M, et al. . Stat3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 2009;206:1465–72.10.1084/jem.20082683
- Sonnenberg GF, Monticelli LA, Elloso MM, et al. . CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011;34:122–34.10.1016/j.immuni.2010.12.009
- Zheng Y, Valdez PA, Danilenko DM, et al. . Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 2008;14:282–9.10.1038/nm1720
- Shkoda A, Ruiz PA, Daniel H, et al. . Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 2007;132:190–207.10.1053/j.gastro.2006.10.030
- Heazlewood CK, Cook MC, Eri R, et al. . Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 2008;5:e5410.1371/journal.pmed.0050054
- Hu S, Ciancio MJ, Lahav M, et al. . Translational inhibition of colonic epithelial heat shock proteins by IFN-gamma and TNF-alpha in intestinal inflammation. Gastroenterology 2007;133:1893–904.10.1053/j.gastro.2007.09.026
- Zha J-M, Li H-S, Lin Q, et al. . Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling. Cell Mol Gastroenterol Hepatol 2019;7:255–74.10.1016/j.jcmgh.2018.09.006
- Pott J, Kabat AM, Maloy KJ. Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice. Cell Host Microbe 2018;23:191–202.10.1016/j.chom.2017.12.017
- Akazawa Y, Isomoto H, Matsushima K, et al. . Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. PLoS One 2013;8:e8232210.1371/journal.pone.0082322
- Lejeune D, Dumoutier L, Constantinescu S, et al. . Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. pathways that are shared with and distinct from IL-10. J Biol Chem 2002;277:33676–82.10.1074/jbc.M204204200
- Kim K, Kim G, Kim J-Y, et al. . Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis 2014;35:1352–61.10.1093/carcin/bgu044
- Afrazi A, Branca MF, Sodhi CP, et al. . Toll-Like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem 2014;289:9584–99.10.1074/jbc.M113.526517
Source: PubMed