Desmoglein 2, but not desmocollin 2, protects intestinal epithelia from injury

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Desmosomes are the least understood intercellular junctions in the intestinal epithelia and provide cell–cell adhesion via the cadherins desmoglein (Dsg)2 and desmocollin (Dsc)2. We studied these cadherins in Crohn’s disease (CD) patients and in newly generated conditional villin-Cre DSG2 and DSC2 knockout mice (DSG2ΔIEC; DSC2ΔIEC). CD patients exhibited altered desmosomes and reduced Dsg2/Dsc2 levels. The intestines of both transgenic animal lines were histopathologically inconspicuous. However, DSG2ΔIEC, but not DSC2ΔIEC mice displayed an increased intestinal permeability, a wider desmosomal space as well as alterations in desmosomal and tight junction components. After dextran sodium sulfate (DSS) treatment and Citrobacter rodentium exposure, DSG2ΔIEC mice developed a more-pronounced colitis, an enhanced intestinal epithelial barrier disruption, leading to a stronger inflammation and activation of epithelial pSTAT3 signaling. No susceptibility to DSS-induced intestinal injury was noted in DSC2ΔIEC animals. Dsg2 interacted with the cytoprotective chaperone Hsp70. Accordingly, DSG2ΔIEC mice had lower Hsp70 levels in the plasma membrane compartment, whereas DSC2ΔIEC mice displayed a compensatory recruitment of galectin 3, a junction-tightening protein. Our results demonstrate that Dsg2, but not Dsc2 is required for the integrity of the intestinal epithelial barrier in vivo.

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  1. 1.

    Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

  2. 2.

    Barmeyer, C., Schulzke, J. D. & Fromm, M. Claudin-related intestinal diseases. Semin. Cell Dev. Biol. 42, 30–38 (2015).

  3. 3.

    Turner, J. R., Buschmann, M. M., Romero-Calvo, I., Sailer, A. & Shen, L. The role of molecular remodeling in differential regulation of tight junction permeability. Semin. Cell Dev. Biol. 36, 204–212 (2014).

  4. 4.

    Capaldo, C. T. & Nusrat, A. Claudin switching: physiological plasticity of the tight Junction. Semin. Cell Dev. Biol. 42, 22–29 (2015).

  5. 5.

    Nekrasova, O. & Green, K. J. Desmosome assembly and dynamics. Trends Cell Biol. 23, 537–546 (2013).

  6. 6.

    Holthofer, B., Windoffer, R., Troyanovsky, S. & Leube, R. E. Structure and function of desmosomes. Int. Rev. Cytol. 264, 65–163 (2007).

  7. 7.

    Wang, H. et al. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nat. Med. 17, 96–104 (2011).

  8. 8.

    Brooke, M. A., Nitoiu, D. & Kelsell, D. P. Cell-cell connectivity: desmosomes and disease. J. Pathol. 226, 158–171 (2012).

  9. 9.

    De Arcangelis, A. et al. Hemidesmosome integrity protects the colon against colitis and colorectal cancer. Gut 66, 1748–1760 (2016).

  10. 10.

    Harrison, O. J. et al. Structural basis of adhesive binding by desmocollins and desmogleins. Proc. Natl Acad. Sci. USA 113, 7160–7165 (2016).

  11. 11.

    Garrod, D. & Chidgey, M. Desmosome structure, composition and function. Biochim. Biophys. Acta 1778, 572–587 (2008).

  12. 12.

    Delva, E., Tucker, D. K. & Kowalczyk, A. P. The desmosome. Cold Spring Harb. Perspect. Biol. 1, a002543 (2009).

  13. 13.

    Kowalczyk, A. P. & Green, K. J. Structure, function, and regulation of desmosomes. Progress. Mol. Biol. Transl. Sci. 116, 95–118 (2013).

  14. 14.

    Kolegraff, K., Nava, P., Helms, M. N., Parkos, C. A. & Nusrat, A. Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/beta-catenin signaling. Mol. Biol. Cell 22, 1121–1134 (2011).

  15. 15.

    Nava, P. et al. Desmoglein-2: a novel regulator of apoptosis in the intestinal epithelium. Mol. Biol. Cell 18, 4565–4578 (2007).

  16. 16.

    Spindler, V. et al. Loss of desmoglein 2 contributes to the pathogenesis of Crohn’s disease. Inflamm. Bowel Dis. 21, 2349–2359 (2015).

  17. 17.

    Raczynski, A. R. et al. Enteric infection with Citrobacter rodentium induces coagulative liver necrosis and hepatic inflammation prior to peak infection and colonic disease. PLoS. ONE 7, e33099 (2012).

  18. 18.

    Ungewiss, H. et al. Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase. Sci. Rep. 7, 6329 (2017).

  19. 19.

    Kamekura, R. et al. Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling. Oncogene 33, 4531–4536 (2014).

  20. 20.

    Jiang, K. et al. Galectin 3 regulates desmoglein-2 and intestinal epithelial intercellular adhesion. J. Biol. Chem. 289, 10510–10517 (2014).

  21. 21.

    Fujiwara, M. et al. Desmocollin-2 alone forms functional desmosomal plaques, with the plaque formation requiring the juxtamembrane region and plakophilins. J. Biochem. 158, 339–353 (2015).

  22. 22.

    Atreya, R. et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat. Med. 20, 313–318 (2014).

  23. 23.

    Kant, S., Holthofer, B., Magin, T. M., Krusche, C. A. & Leube, R. E. Desmoglein 2-dependent arrhythmogenic cardiomyopathy is caused by a loss of adhesive function. Circ. Cardiovasc. Genet. 8, 553–563 (2015).

  24. 24.

    Lowndes, M. et al. Different roles of cadherins in the assembly and structural integrity of the desmosome complex. J. Cell Sci. 127, 2339–2350 (2014).

  25. 25.

    Sumigray, K. D. & Lechler, T. Desmoplakin controls microvilli length but not cell adhesion or keratin organization in the intestinal epithelium. Mol. Biol. Cell 23, 792–799 (2012).

  26. 26.

    Thomason, H. A., Scothern, A., McHarg, S. & Garrod, D. R. Desmosomes: adhesive strength and signalling in health and disease. Biochem. J. 429, 419–433 (2010).

  27. 27.

    Nie, Z., Merritt, A., Rouhi-Parkouhi, M., Tabernero, L. & Garrod, D. Membrane-impermeable cross-linking provides evidence for homophilic, isoform-specific binding of desmosomal cadherins in epithelial cells. J. Biol. Chem. 286, 2143–2154 (2011).

  28. 28.

    Samborski, P. & Grzymislawski, M. The role of HSP70 heat shock proteins in the pathogenesis and treatment of inflammatory bowel diseases. Adv. Clin. Exp. Med. 24, 525–530 (2015).

  29. 29.

    Tanaka, K. et al. Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis. J. Biol. Chem. 282, 23240–23252 (2007).

  30. 30.

    Osmani, N. & Labouesse, M. Remodeling of keratin-coupled cell adhesion complexes. Curr. Opin. Cell Biol. 32, 30–38 (2015).

  31. 31.

    Hatzfeld, M., Keil, R. & Magin, T. M. Desmosomes and intermediate filaments: their consequences for tissue mechanics. Cold Spring Harb. Perspect. Biol. 9, a029157 (2017).

  32. 32.

    Otsuka, M. et al. Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology 138, 1255–1265 (2010).

  33. 33.

    Kojouharoff, G. et al. Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin. Exp. Immunol. 107, 353–358 (1997).

  34. 34.

    Goncalves, N. S. et al. Critical role for tumor necrosis factor alpha in controlling the number of lumenal pathogenic bacteria and immunopathology in infectious colitis. Infect. Immun. 69, 6651–6659 (2001).

  35. 35.

    Poritz, L. S. et al. Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J. Surg. Res. 140, 12–19 (2007).

  36. 36.

    Flynn, A. N. & Buret, A. G. Tight junctional disruption and apoptosis in an in vitro model of Citrobacter rodentium infection. Microb. Pathog. 45, 98–104 (2008).

  37. 37.

    Nighot, P. et al. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G988–G997 (2015).

  38. 38.

    Schlegel, N. et al. Desmoglein 2-mediated adhesion is required for intestinal epithelial barrier integrity. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G774–G783 (2010).

  39. 39.

    Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).

  40. 40.

    Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014).

  41. 41.

    Carvalho, F. A. et al. Interleukin-1beta (IL-1beta) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis. Gut 61, 373–384 (2012).

  42. 42.

    Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug. Discov. 13, 21–38 (2014).

  43. 43.

    Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

  44. 44.

    Leffler, D. A. et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology 148, 1311–1319 e1316 (2015).

  45. 45.

    el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004).

  46. 46.

    Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).

  47. 47.

    Rimpler U. Funktionelle Charakterisierung von Desmocollin 2 während der Embryonalentwicklung und im adulten Herzen in der Maus. Humboldt University zu Berlin (2014).

  48. 48.

    Schauer, D. B. & Falkow, S. The eae gene of Citrobacter freundii biotype 4280 is necessary for colonization in transmissible murine colonic hyperplasia. Infect. Immun. 61, 4654–4661 (1993).

  49. 49.

    Meir, M. et al. Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G613–G624 (2015).

  50. 50.

    Chinen, T. et al. Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance. Nat. Commun. 2, 190 (2011).

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We are thankful to Shintaro T. Suzuki for providing the DLD1 cell lines and Adam Breitscheidel for his assistance with figure preparation. The expert technical assistance of Linda Schaub, Ingrid Breuer, Silvia Roubrocks, Ana Mandić, Sandra Jumpertz, Sabine Eisner, and Silvia Koch is gratefully acknowledged. Our work was supported by a grant from the Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University, by Else Kröner Exzellenzstipendium (to P.S.), by the Deutsche Forschungsgemeinschaft (DFG) SFB TRR57 (to PS, PB, and CT), SFB 985 (to PS and CT), and by the German Federal Ministry of Education and Research (BMBF01GM1518A to PB). The research on epithelial junctions is supported by the DFG Priority Program SPP 1782 to NS, PS, RL, and JW.

Author information

Study was planned and designed by A.G., R.E.L. and P.S. and the acquisition of data was performed by A.G., L.A.P.P., G.M.S., M.M., P.B., H.U. and C.P. Analysis and interpretation of data were conducted by A.G., N.S., P.B., G.S., R.E.L., J.W., P.S. and C.P. A.G. and P.S. drafted the manuscript and all authors contributed to the critical revision of the manuscript for important intellectual content. Statistical analysis was performed by A.G. and P.S., who also obtained the funding and supervised the study. S.K., C.A.K., G.S., C.T., R.E.L., N.G. and A.H. provided technical or material support.

Correspondence to Pavel Strnad.

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