Skip to main content

Advertisement

Springer Nature Link
Log in

Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome

  • Immunology & Microbiology in Miami
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Langerhans cells (LCs) are a specialized subset of epidermal dendritic cells. They represent one of the first cells of immunologic barrier and play an important role during the inflammatory phase of acute wound healing. Despite considerable progress in our understanding of the immunopathology of diabetes mellitus and its associated comorbidities such as diabetic foot ulcers (DFUs), considerable gaps in our knowledge exist. In this study, we utilized the human ex vivo wound model and confirmed the increased epidermal LCs at wound edges during early phases of wound healing. Next, we aimed to determine differences in quantity of LCs between normal human and diabetic foot skin and to learn if the presence of LCs correlates with the healing outcome in DFUs. We utilized immunofluorescence to detect CD207+ LCs in specimens from normal and diabetic foot skin and DFU wound edges. Specimens from DFUs were collected at the initial visit and 4 weeks later at the time when the healing outcome was determined. DFUs that decreased in size by >50 % were considered to be healing, while DFUs with a size reduction of <50 % were considered non-healing. Quantitative assessment of LCs showed a higher number of LCs in healing when compared to non-healing DFU’s. Our findings provide evidence that LCs are present in higher number in diabetic feet than normal foot skin. Healing DFUs show a higher number of LCs compared to non-healing DFUs. These findings indicate that the epidermal immune barrier plays an important role in the DFU healing outcome and may offer new therapeutic avenues targeting LC in non-healing DFUs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gallo PM, Gallucci S. The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013;4:138. doi:10.3389/fimmu.2013.00138.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med. 2012;209(6):1167–81. doi:10.1084/jem.20120340.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3(12):1135–41. doi:10.1038/ni852.

    Article  CAS  PubMed  Google Scholar 

  4. Valladeau J, Ravel O, Dezutter-Dambuyant C, Moore K, Kleijmeer M, Liu Y, et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000;12(1):71–81.

    Article  CAS  PubMed  Google Scholar 

  5. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52. doi:10.1038/32588.

    Article  CAS  PubMed  Google Scholar 

  6. Strbo N, Yin N, Stojadinovic O. Innate and adaptive immune responses in wound epithelialization. Advances in Wound Care. 2013.

  7. Igyarto BZ, Kaplan DH. The evolving function of Langerhans cells in adaptive skin immunity. Immunol Cell Biol. 2010;88(4):361–5. doi:10.1038/icb.2010.24.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Geissmann F, Prost C, Monnet JP, Dy M, Brousse N, Hermine O. Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J Exp Med. 1998;187(6):961–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C, et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol. 2003;4(4):380–6. doi:10.1038/ni903.

    Article  CAS  PubMed  Google Scholar 

  10. Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D, et al. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 2004;23(4):969–79. doi:10.1038/sj.emboj.7600085.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46. doi:10.1056/NEJM199909023411006.

    Article  CAS  PubMed  Google Scholar 

  12. Jameson JM, Sharp LL, Witherden DA, Havran WL. Regulation of skin cell homeostasis by gamma delta T cells. Front Biosci. 2004;9:2640–51.

    Article  CAS  PubMed  Google Scholar 

  13. Noli C, Miolo A. The mast cell in wound healing. Vet Dermatol. 2001;12(6):303–13.

    Article  CAS  PubMed  Google Scholar 

  14. Juhasz I, Simon M Jr, Herlyn M, Hunyadi J. Repopulation of Langerhans cells during wound healing in an experimental human skin/SCID mouse model. Immunol Lett. 1996;52(2–3):125–8.

    Article  CAS  PubMed  Google Scholar 

  15. Helfman T, Streilein JW, Eaglstein WH, Mertz PM. Studies on the repopulation of Langerhans cells in partial-thickness wounds. Air exposed and occlusively dressed. Arch Dermatol. 1993;129(5):592–5.

    Article  CAS  PubMed  Google Scholar 

  16. Reiber GE. The epidemiology of diabetic foot problems. Diabet Med. 1996;13(Suppl 1):S6–11.

    PubMed  Google Scholar 

  17. Reiber GE, Ledous WE. Epidemiology of diabetic foot ulcers and amputations: evidence for prevention. In: Williams R, Herman W, Kinmonth A-L, editors. The evidence base for diabetes care. London: Wiley; 2002. p. 641–65.

    Chapter  Google Scholar 

  18. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care. 1990;13(5):513–21.

    Article  CAS  PubMed  Google Scholar 

  19. Boyko EJ, Ahroni JH, Smith DG, Davignon D. Increased mortality associated with diabetic foot ulcer. Diabet Med. 1996;13(11):967–72. doi:10.1002/(SICI)1096-9136(199611)13:11<967:AID-DIA266>3.0.CO;2-K.

    Article  CAS  PubMed  Google Scholar 

  20. Tellechea A, Kafanas A, Leal EC, Tecilazich F, Kuchibhotla S, Auster ME, et al. Increased skin inflammation and blood vessel density in human and experimental diabetes. Int J Low Extrem Wounds. 2013;12(1):4–11. doi:10.1177/1534734612474303.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Casanova-Molla J, Morales M, Planas-Rigol E, Bosch A, Calvo M, Grau-Junyent JM, et al. Epidermal Langerhans cells in small fiber neuropathies. Pain. 2012;153(5):982–9. doi:10.1016/j.pain.2012.01.021.

    Article  PubMed  Google Scholar 

  22. Rosner K, Ross C, Karlsmark T, Petersen AA, Gottrup F, Vejlsgaard GL. Immunohistochemical characterization of the cutaneous cellular infiltrate in different areas of chronic leg ulcers. APMIS: Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 1995;103(4):293–9.

    Article  CAS  PubMed  Google Scholar 

  23. Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol. 1998;111(5):850–7. doi:10.1046/j.1523-1747.1998.00381.x.

    Article  CAS  PubMed  Google Scholar 

  24. Galkowska H, Wojewodzka U, Olszewski WL. Low recruitment of immune cells with increased expression of endothelial adhesion molecules in margins of the chronic diabetic foot ulcers. Wound Repair Regen. 2005;13(3):248–54. doi:10.1111/j.1067-1927.2005.130306.x.

    Article  PubMed  Google Scholar 

  25. Stojadinovic O, Landon JN, Gordon KA, Pastar I, Escandon J, Vivas A, et al. Quality assessment of tissue specimens for studies of diabetic foot ulcers. Exp Dermatol. 2013;22(3):216–8. doi:10.1111/exd.12104.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Berger CL, Vasquez JG, Shofner J, Mariwalla K, Edelson RL. Langerhans cells: mediators of immunity and tolerance. Int J Biochem Cell Biol. 2006;38(10):1632–6. doi:10.1016/j.biocel.2006.03.006.

    Article  CAS  PubMed  Google Scholar 

  27. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26(6):1879–82.

    Article  PubMed  Google Scholar 

  28. Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167(1):59–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Lee B, Vouthounis C, Stojadinovic O, Brem H, Im M, Tomic-Canic M. From an enhance some to a repress some: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol. 2005;345(5):1083–97. doi:10.1016/j.jmb.2004.11.027.

    Article  CAS  PubMed  Google Scholar 

  30. Stojadinovic O, Lee B, Vouthounis C, Vukelic S, Pastar I, Blumenberg M, et al. Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. J Biol Chem. 2007;282(6):4021–34. doi:10.1074/jbc.M606262200.

    Article  CAS  PubMed  Google Scholar 

  31. Tomic-Canic M, Mamber SW, Stojadinovic O, Lee B, Radoja N, McMichael J. Streptolysin O enhances keratinocyte migration and proliferation and promotes skin organ culture wound healing in vitro. Wound Repair Regen. 2007;15(1):71–9. doi:10.1111/j.1524-475X.2006.00187.x.

    Article  PubMed  Google Scholar 

  32. Stojadinovic O, Tomic-Canic M. Human ex vivo wound healing model. Methods Mol Biol. 2013;1037:255–64. doi:10.1007/978-1-62703-505-7_14.

    Article  PubMed  Google Scholar 

  33. Wang CQ, Cruz-Inigo AE, Fuentes-Duculan J, Moussai D, Gulati N, Sullivan-Whalen M, et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS ONE. 2011;6(4):e18907. doi:10.1371/journal.pone.0018907.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Asahina A, Tamaki K. Role of Langerhans cells in cutaneous protective immunity: is the reappraisal necessary? J Dermatol Sci. 2006;44(1):1–9. doi:10.1016/j.jdermsci.2006.07.002.

    Article  CAS  PubMed  Google Scholar 

  35. Galkowska H, Olszewski WL, Wojewodzka U. Expression of natural antimicrobial peptide beta-defensin-2 and Langerhans cell accumulation in epidermis from human non-healing leg ulcers. Folia Histochem Cytobiol. 2005;43(3):133–6.

    CAS  PubMed  Google Scholar 

  36. Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol. 2008;8(12):935–47. doi:10.1038/nri2455.

    Article  CAS  PubMed  Google Scholar 

  37. Potten CS, Allen TD. A model implicating the Langerhans cell in keratinocyte proliferation control. Differentiation. 1976;5(1):43–7.

    Article  CAS  PubMed  Google Scholar 

  38. Hostetter MK. Handicaps to host defense. Effects of hyperglycemia on C3 and Candida albicans. Diabetes. 1990;39(3):271–5.

    Article  CAS  PubMed  Google Scholar 

  39. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am. 1995;9(1):1–9.

    CAS  PubMed  Google Scholar 

  40. Koh GC, Peacock SJ, van der Poll T, Wiersinga WJ. The impact of diabetes on the pathogenesis of sepsis. Eur J Clin Microbiol Infect Dis. 2012;31(4):379–88. doi:10.1007/s10096-011-1337-4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Pastar I, Stojadinovic O, Tomic-Canic M. Role of keratinocytes in healing of chronic wounds. Surg Technol Int. 2008;17:105–12.

    PubMed  Google Scholar 

  42. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601. doi:10.1111/j.1524-475X.2008.00410.x.

    Article  PubMed  Google Scholar 

  43. Nakamura K, Williams IR, Kupper TS. Keratinocyte-derived monocyte chemoattractant protein 1 (MCP-1): analysis in a transgenic model demonstrates MCP-1 can recruit dendritic and Langerhans cells to skin. J Invest Dermatol. 1995;105(5):635–43.

    Article  CAS  PubMed  Google Scholar 

  44. Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, et al. Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol. 2001;159(2):457–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Kaplan DH, Jenison MC, Saeland S, Shlomchik WD, Shlomchik MJ. Epidermal Langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity. 2005;23(6):611–20. doi:10.1016/j.immuni.2005.10.008.

    Article  CAS  PubMed  Google Scholar 

  46. Romani N, Koide S, Crowley M, Witmer-Pack M, Livingstone AM, Fathman CG, et al. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J Exp Med. 1989;169(3):1169–78.

    Article  CAS  PubMed  Google Scholar 

  47. Stoitzner P, Tripp CH, Eberhart A, Price KM, Jung JY, Bursch L, et al. Langerhans cells cross-present antigen derived from skin. Proc Natl Acad Sci USA. 2006;103(20):7783–8. doi:10.1073/pnas.0509307103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Lutz MB, Dohler A, Azukizawa H. Revisiting the tolerogenicity of epidermal Langerhans cells. Immunol Cell Biol. 2010;88(4):381–6. doi:10.1038/icb.2010.17.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr Anthony LaBruna and Dr Thomas Zwick for providing skin specimens, and Shailee Patel and members of the Wound Healing Clinical Research Team for technical assistance. This work is supported by National Institutes of Health (DK086364; NR013881) to MT-C.

Author information

Authors and Affiliations

  1. Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL, 33136, USA

    Olivera Stojadinovic, Natalie Yin, Irena Pastar, Robert S. Kirsner & Marjana Tomic-Canic

  2. Department of Dermatology, Venerology, Allergology University Medical Center, Goettingen Room 01/C4/851 Robert-Koch Straße 40, 37075, Goettingen, Germany

    Janin Lehmann

Authors
  1. Olivera Stojadinovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalie Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Janin Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Irena Pastar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert S. Kirsner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marjana Tomic-Canic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marjana Tomic-Canic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stojadinovic, O., Yin, N., Lehmann, J. et al. Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome. Immunol Res 57, 222–228 (2013). https://doi.org/10.1007/s12026-013-8474-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-013-8474-z

Keywords

Search

Navigation