Advertisement

Malt1 inactivation attenuates experimental colitis through the regulation of Th17 and Th1/17 cells

  • Yoshiki Nakamura
  • Keiko Igaki
  • Yusaku Komoike
  • Kazumasa Yokoyama
  • Noboru TsuchimoriEmail author
Original Research Paper
  • 91 Downloads

Abstract

Objective and design

Protease activity of MALT lymphoma-translocation protein 1 (Malt1) plays an important role in the development of colitis, but the detailed mechanism has not been fully elucidated.

Method

Effects of Malt1 protease on the activation of T cells and the development of experimental colitis was investigated using Malt1 protease-deficient (PD) mouse.

Results

IL-2 production from CD4+ T cells of Malt1 PD mice was decreased compared with that of wild-type (WT) mice. Intraperitoneal injection of anti-CD3 antibody into Malt1 PD mouse induced less productions of IL-17 in the plasma, as well as the colonic gene expression of IL-17A, compared with WT mice, whereas IFN-γ production was not impaired. In naïve T-cell transfer colitis model, Malt1 PD T cells induced less disease severity than WT T cells. Then, reduction in the populations of Th17 and Th1/17 cells was observed in the mesenteric lymph nodes of the recipient mice transferred with Malt1 PD T cells, whereas those of Th1 cells were not impaired. IL-17A expression in the colon was also decreased in the mouse receiving Malt1 PD T cells.

Conclusions

Inactivation of Malt1 protease activity abrogates Th17 and Th1/17 cell activation, resulting in the amelioration of experimental colitis.

Keywords

Malt1 Experimental colitis Th17 cells Th1/17 cells IL-17 

Notes

Acknowledgements

We thank the following employees of Takeda Pharmaceutical Company Limited, Naoko Matsunaga and Takeo Arita, for contributing to discussion on in vivo experiment, Hikaru Saito for contributing to in vivo experiment, and Kimihiko Iwachidow, Takashi Yano, and Yuki Nakamura for contributing to generation, breeding and supply of Malt1 PD mouse.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11_2018_1207_MOESM1_ESM.docx (458 kb)
Supplementary material 1 (DOCX 458 KB)

References

  1. 1.
    Pithadia AB, Jain S. Treatment of inflammatory bowel disease (IBD). Pharmacol Rep. 2011;63(3):629–42.CrossRefGoogle Scholar
  2. 2.
    Mozaffari S, Nikfar S, Abdolghaffari AH, Abdollahi M. New biologic therapeutics for ulcerative colitis and Crohn’s disease. Expert Opin Biol Ther. 2014;14(5):583–600.  https://doi.org/10.1517/14712598.2014.885945.CrossRefPubMedGoogle Scholar
  3. 3.
    Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711–21.  https://doi.org/10.1056/NEJMoa1215739.CrossRefPubMedGoogle Scholar
  4. 4.
    Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(3):618 – 27.e3.  https://doi.org/10.1053/j.gastro.2014.05.008.CrossRefPubMedGoogle Scholar
  5. 5.
    Peyrin-Biroulet L, Danese S, Argollo M, Pouillon L, Peppas S, Gonzalez-Lorenzo M, et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with Crohn’s disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2018.  https://doi.org/10.1016/j.cgh.2018.06.026.CrossRefGoogle Scholar
  6. 6.
    Wong U, Cross RK. Primary and secondary nonresponse to infliximab: mechanisms and countermeasures. Expert Opin Drug Metab Toxicol. 2017;13(10):1039–46.  https://doi.org/10.1080/17425255.2017.1377180.CrossRefPubMedGoogle Scholar
  7. 7.
    Feagan BG, Sandborn WJ, D’Haens G, Panes J, Kaser A, Ferrante M, 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(10080):1699–709.  https://doi.org/10.1016/s0140-6736(17)30570-6.CrossRefPubMedGoogle Scholar
  8. 8.
    Hoeve MA, Savage ND, de Boer T, Langenberg DM, de Waal Malefyt R, Ottenhoff TH, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol. 2006;36(3):661–70.  https://doi.org/10.1002/eji.200535239.CrossRefPubMedGoogle Scholar
  9. 9.
    Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Investig. 2006;116(5):1218–22.  https://doi.org/10.1172/jci28508.CrossRefPubMedGoogle Scholar
  10. 10.
    Chen Y, Chauhan SK, Shao C, Omoto M, Inomata T, Dana R. IFN-gamma-expressing Th17 cells are required for development of severe ocular surface autoimmunity. J Immunol. 2017.  https://doi.org/10.4049/jimmunol.1602144.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Globig AM, Hennecke N, Martin B, Seidl M, Ruf G, Hasselblatt P, et al. Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-gamma+ IL-17+ coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(12):2321–9.  https://doi.org/10.1097/mib.0000000000000210.CrossRefPubMedGoogle Scholar
  12. 12.
    Kanai T, Mikami Y, Sujino T, Hisamatsu T, Hibi T. RORgammat-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation. Mucosal Immunol. 2012;5(3):240–7.  https://doi.org/10.1038/mi.2012.6.CrossRefPubMedGoogle Scholar
  13. 13.
    Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009;66(3):390–402.  https://doi.org/10.1002/ana.21748.CrossRefPubMedGoogle Scholar
  14. 14.
    Ruland J, Duncan GS, Wakeham A, Mak TW. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity. 2003;19(5):749–58.CrossRefGoogle Scholar
  15. 15.
    Rosebeck S, Rehman AO, Lucas PC, McAllister-Lucas LM. From MALT lymphoma to the CBM signalosome: three decades of discovery. Cell Cycle. 2011;10(15):2485–96.CrossRefGoogle Scholar
  16. 16.
    Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, et al. Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci USA. 2011;108(35):14596–601.  https://doi.org/10.1073/pnas.1105020108.CrossRefPubMedGoogle Scholar
  17. 17.
    Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P, et al. T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J. 2011;30(9):1742–52.  https://doi.org/10.1038/emboj.2011.85.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 2008;9(3):263–71.  https://doi.org/10.1038/ni1561.CrossRefPubMedGoogle Scholar
  19. 19.
    Jaworski M, Marsland BJ, Gehrig J, Held W, Favre S, Luther SA, et al. Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. EMBO J. 2014;33(23):2765–81.  https://doi.org/10.15252/embj.201488987.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nakamura Y, Yokoyama K, Igaki K, Tsuchimori N. Role of Malt1 protease activity in pathogenesis of inflammatory disorders mediated by FcgammaR signaling. Int Immunopharmacol. 2018;56:193–6.  https://doi.org/10.1016/j.intimp.2018.01.028.CrossRefPubMedGoogle Scholar
  21. 21.
    Shibata A, Uga K, Sato T, Sagara M, Igaki K, Nakamura Y, et al. Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORgammat inverse agonist. Biochem Pharmacol. 2018;150:35–45.  https://doi.org/10.1016/j.bcp.2018.01.023.CrossRefPubMedGoogle Scholar
  22. 22.
    Maxwell JR, Zhang Y, Brown WA, Smith CL, Byrne FR, Fiorino M, et al. Differential roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity. 2015;43(4):739–50.  https://doi.org/10.1016/j.immuni.2015.08.019.CrossRefPubMedGoogle Scholar
  23. 23.
    Igaki K, Nakamura Y, Komoike Y, Uga K, Shibata A, Ishimura Y, et al. Pharmacological evaluation of TAK-828F, a novel orally available RORgammat inverse agonist, on murine colitis model. Inflammation. 2018.  https://doi.org/10.1007/s10753-018-0875-7.CrossRefPubMedGoogle Scholar
  24. 24.
    Kara EE, McKenzie DR, Bastow CR, Gregor CE, Fenix KA, Ogunniyi AD, et al. CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells. Nat Commun. 2015;6:8644.  https://doi.org/10.1038/ncomms9644.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Uo M, Hisamatsu T, Miyoshi J, Kaito D, Yoneno K, Kitazume MT, et al. Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcgammaR-mediated CD14 macrophage activation. Gut. 2013;62(12):1734–44.  https://doi.org/10.1136/gutjnl-2012-303063.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Yoshiki Nakamura
    • 1
    • 2
  • Keiko Igaki
    • 1
    • 3
  • Yusaku Komoike
    • 1
  • Kazumasa Yokoyama
    • 1
  • Noboru Tsuchimori
    • 1
    Email author
  1. 1.Pharmaceutical Research DivisionTakeda Pharmaceutical Company, LimitedFujisawaJapan
  2. 2.Pharmaceutical SciencesTakeda Pharmaceutical Company, LimitedFujisawaJapan
  3. 3.Axcelead Drug Discovery Partners, Inc.FujisawaJapan

Personalised recommendations