Differential regulation of claudin-2 and claudin-15 expression in children and adults with malabsorptive disease

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Abstract

Intestinal Na+-nutrient cotransport depends on claudin-2 and claudin-15 mediated Na+ recycling. Expression of these proteins is coordinately regulated during postnatal development. While expression of claudin-2 and claudin-15 has been studied in inflammatory bowel disease (IBD) and celiac disease (CD), it has not been assessed in other malabsorptive diseases, and no reports have compared expression in children and adults. We used quantitative immunofluorescence microscopy to assess claudin-2 and claudin-15 expression in duodenal biopsies from children and adults with malabsorptive disease and healthy controls. Consistent with previous work in rodents, claudin-2 expression in healthy children was markedly greater, and claudin-15 expression was less, than that in adults. Claudin-2 expression was increased in adults with CD and downregulated in children with graft-versus-host disease (GVHD). In contrast, claudin-15 expression was reduced in adults with GVHD and common variable immunodeficiency (CVID). These data show that one of the two Na+/water pore-forming claudins is upregulated in CD and downregulated in GVHD and CVID. The specific claudin whose expression changes, however, reflects the age of the patient (child or adult). We conclude that contributions of claudin-2 and claudin-15 to pathophysiology of and responses to diarrhea in children and adults with GVHD and CVID differ from those in CD and IBD.

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References

  1. 1.

    Tamura A, Hayashi H, Imasato M, et al. Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterol. 2011;140:913–23.

  2. 2.

    Wada M, Tamura A, Takahashi N, et al. Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. Gastroenterol. 2013;144:369–80.

  3. 3.

    Muto S, Hata M, Taniguchi J, et al. Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci USA. 2010;107:8011–6.

  4. 4.

    Tamura A, Kitano Y, Hata M, et al. Megaintestine in claudin-15-deficient mice. Gastroenterol. 2008;134:523–34.

  5. 5.

    Turner JR, Black ED. NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)- glucose cotransport in intestinal epithelia. Am J Physiol Cell Physiol. 2001;281:C1533–1541.

  6. 6.

    Lin R, Murtazina R, Cha B, et al. D-glucose acts via sodium/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+/H+ exchange regulatory factor 2- dependent process. Gastroenterol. 2011;140:560–71.

  7. 7.

    Holmes JL, Van Itallie CM, Rasmussen JE, et al. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns. 2006;6:581–8.

  8. 8.

    Weber CR, Nalle SC, Tretiakova M, et al. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab Investig. 2008;88:1110–20.

  9. 9.

    Luettig J, Rosenthal R, Barmeyer C, et al. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers. 2015;3:e977176.

  10. 10.

    Schumann M, Gunzel D, Buergel N, et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut. 2012;61:220–8.

  11. 11.

    Szakal DN, Gyorffy H, Arato A, et al. Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch. 2010;456:245–50.

  12. 12.

    Kohout P. Small bowel permeability in diagnosis of celiac disease and monitoring of compliance of a gluten-free diet (gut permeability in celiac disease). Acta Medica. 2001;44:101–4.

  13. 13.

    Nalle SC, Kwak HA, Edelblum KL, et al. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med. 2014;6:243ra287.

  14. 14.

    Nalle SC, Turner JR. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease. Mucosal Immunol. 2015;8:720–30.

  15. 15.

    Koltun WA, Bloomer MM, Colony P, et al. Increased intestinal permeability in rats with graft versus host disease. Gut. 1996;39:291–8.

  16. 16.

    Green PH, Jabri B. Celiac disease. Annu Rev Med. 2006;57:207–21.

  17. 17.

    Guandalini S, Assiri A. Celiac disease: a review. JAMA Pediatr. 2014;168:272–8.

  18. 18.

    Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–43.

  19. 19.

    Diosdado B, van Bakel H, Strengman E, et al. Neutrophil recruitment and barrier impairment in celiac disease: a genomic study. Clin Gastroenterol Hepatol. 2007;5:574–81.

  20. 20.

    Calleja S, Vivas S, Santiuste M, et al. Dynamics of non-conventional intraepithelial lymphocytes-NK, NKT, and gammadelta T-in celiac Disease: relationship with age, diet, and histopathology. Dig Dis Sci. 2011;56:2042–9.

  21. 21.

    McAllister CS, Kagnoff MF. The immunopathogenesis of celiac disease reveals possible therapies beyond the gluten-free diet. Semin Immunopathol. 2012;34:581–600.

  22. 22.

    Cogbill CH, Drobyski WR, Komorowski RA. Gastrointestinal pathology of autologous graft-versus-host disease following hematopoietic stem cell transplantation: a clinicopathological study of 17 cases. Mod Pathol. 2011;24:117–25.

  23. 23.

    Sivula J, Cordova ZM, Tuimala J, et al. Toll-like receptor gene polymorphisms confer susceptibility to graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Scand J Immunol. 2012;76:336–41.

  24. 24.

    Washington K, Jagasia M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum Pathol. 2009;40:909–17.

  25. 25.

    Sung D, Iuga AC, Kato T, et al. Crypt apoptotic body counts in normal ileal biopsies overlap with graft-versus-host disease and acute cellular rejection of small bowel allografts. Hum Pathol. 2016;56:89–92.

  26. 26.

    Daniels JA, Lederman HM, Maitra A, et al. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31:1800–12.

  27. 27.

    Washington K, Stenzel TT, Buckley RH, et al. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20:1240–52.

  28. 28.

    Rosenthal R, Gunzel D, Piontek J, et al. Claudin-15 forms a water channel through the tight junction with distinct function compared to claudin-2. Acta Physiol. 2019;12:e13334.

  29. 29.

    Tsai PY, Zhang B, He WQ, et al. IL-22 upregulates epithelial claudin-2 to drive diarrhea and enteric pathogen clearance. Cell Host Microbe. 2017;21:671–81 e674.

  30. 30.

    Schumann M, Siegmund B, Schulzke JD, et al. Celiac Disease: role of the epithelial barrier. Cell Mol Gastroenterol Hepatol. 2017;3:150–62.

  31. 31.

    Heller F, Florian P, Bojarski C. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129:550–64.

  32. 32.

    Weber CR, Raleigh DR, Su L, et al. Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J Biol Chem. 2010;285:12037–46.

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Acknowledgements

This work was supported by National Institutes of Health (R01DK61631, R01DK68271, R24DK099803), the Harvard Digestive Disease Center (P30DK034854), and the University of Chicago Cancer Center (P30CA014599). AS and JRT were involved in case acquisition and tissue microarray development; MLDM, SPN, SY, and JRT were involved in data acquisition and analysis, figure preparation, and paper creation. All authors approved the final paper.

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Correspondence to Jerrold R. Turner.

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Ong, M.L.D.M., Yeruva, S., Sailer, A. et al. Differential regulation of claudin-2 and claudin-15 expression in children and adults with malabsorptive disease. Lab Invest (2019) doi:10.1038/s41374-019-0324-8

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