Skip to main content

Advertisement

SpringerLink
Log in

Regulation of Langerhans cell functions in a hypoxic environment

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Langerhans cells (LCs) are a specialized dendritic cell subset that resides in the epidermis and mucosal epithelia and is critical for the orchestration of skin immunity. Recent evidence suggest that LCs are involved in aberrant wound healing and in the development of hypertrophic scars and chronic wounds, which are characterized by a hypoxic environment. Understanding LCs biology under hypoxia may, thus, lead to the identification of novel pathogenetic mechanisms of wound repair disorders and open new therapeutic opportunities to improve wound healing. In this study, we characterize a previously unrecognized role for hypoxia in significantly affecting the phenotype and functional properties of human monocyte-derived LCs, impairing their ability to stimulate naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)-1, a member of the Ig immunoregulatory receptor family, as a new hypoxia-inducible gene in LCs and an activator of their proinflammatory and Th1-polarizing functions in a hypoxic environment. Furthermore, we provide the first evidence of TREM-1 expression in vivo in LCs infiltrating hypoxic areas of active hypertrophic scars and decubitous ulcers, pointing to a potential pathogenic role of this molecule in wound repair disorders.

Key messages

  • Hypoxia modulates surface molecule expression and cytokine profile in Langerhans cells.

  • Hypoxia impairs human Langerhans cell stimulatory activity on naive T cells.

  • Hypoxia selectively induces TREM-1 expression in human Langerhans cells.

  • TREM-1 engagement stimulates Langerhans cell inflammatory and Th1-polarizing activity.

  • TREM-1 is expressed in vivo in Langerhans cells infiltrating hypoxic skin lesions.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Romani N, Clausen BE, Stoitzner P (2010) Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol Rev 234:120–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Merad M, Ginhoux F, Collin M (2008) Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol 8:935–947

    Article  CAS  PubMed  Google Scholar 

  3. Borkowski TA, Letterio JJ, Farr AG, Udey MC (1996) A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J Exp Med 184:2417–2422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Geissmann F, Dieu-Nosjean MC, Dezutter C, Valladeau J, Kayal S, Leborgne M, Brousse N, Saeland S, Davoust J (2002) Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J Exp Med 196:417–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, Di Pucchio T, Connolly J, Fay JW, Pascual V et al (2007) Dendritic cell subsets in health and disease. Immunol Rev 219:118–142

    Article  CAS  PubMed  Google Scholar 

  6. Lin A, Schildknecht A, Nguyen LT, Ohashi PS (2010) Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth. Immunol Lett 127:77–84

    Article  CAS  PubMed  Google Scholar 

  7. Musso T, Scutera S, Vermi W, Daniele R, Fornaro M, Castagnoli C, Alotto D, Ravanini M, Cambieri I, Salogni L et al (2008) Activin A induces Langerhans cell differentiation in vitro and in human skin explants. PLoS One 3:e3271

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, Paik KJ, Duscher D, Gurtner GC, Lorenz HP et al (2014) The role of hypoxia-inducible factor in wound healing. Adv Wound Care (New Rochelle) 3:390–399

    Article  Google Scholar 

  9. Rezvani HR, Ali N, Nissen LJ, Harfouche G, de Verneuil H, Taieb A, Mazurier F (2011) HIF-1alpha in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Invest Dermatol 131:1793–1805

    Article  CAS  PubMed  Google Scholar 

  10. Semenza GL (2011) Oxygen sensing, homeostasis, and disease. N Engl J Med 365:537–547

    Article  CAS  PubMed  Google Scholar 

  11. Bosco MC, Varesio L (2014) Hypoxia and gene expression. In: Melillo G (ed) Hypoxia and Cancer. Biological Implications and Therapeutic Opportunities. Humana Press, pp 91-119

  12. Niessen FB, Schalkwijk J, Vos H, Timens W (2004) Hypertrophic scar formation is associated with an increased number of epidermal Langerhans cells. J Pathol 202:121–129

    Article  PubMed  Google Scholar 

  13. Stojadinovic O, Yin N, Lehmann J, Pastar I, Kirsner RS, Tomic-Canic M (2013) Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome. Immunol Res 57:222–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Colonna M, Nakajima H, Cella M (2000) A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol 12:121–127

    Article  CAS  PubMed  Google Scholar 

  15. Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Colonna M, Facchetti F (2003) TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. J Infect Dis 187(Suppl 2):S397–S401

    Article  CAS  PubMed  Google Scholar 

  17. Pelham CJ, Pandya AN, Agrawal DK (2014) Triggering receptor expressed on myeloid cells receptor family modulators: a patent review. Expert Opin Ther Pat 1-13

  18. Bosco MC, Pierobon D, Blengio F, Raggi F, Vanni C, Gattorno M, Eva A, Novelli F, Cappello P, Giovarelli M et al (2011) Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood 117:2625–2639

    Article  CAS  PubMed  Google Scholar 

  19. Castagnoli C, Trombotto C, Ariotti S, Millesimo M, Ravarino D, Magliacani G, Ponzi AN, Stella M, Teich-Alasia S, Novelli F et al (1999) Expression and role of IL-15 in post-burn hypertrophic scars. J Invest Dermatol 113:238–245

    Article  CAS  PubMed  Google Scholar 

  20. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  CAS  PubMed  Google Scholar 

  21. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763

    Article  CAS  PubMed  Google Scholar 

  22. Sun J, Zhang Y, Yang M, Zhang Y, Xie Q, Li Z, Dong Z, Yang Y, Deng B, Feng A et al (2010) Hypoxia induces T-cell apoptosis by inhibiting chemokine C receptor 7 expression: the role of adenosine receptor A(2). Cell Mol Immunol 7:77–82

    Article  CAS  PubMed  Google Scholar 

  23. Roiniotis J, Dinh H, Masendycz P, Turner A, Elsegood CL, Scholz GM, Hamilton JA (2009) Hypoxia prolongs monocyte/macrophage survival and enhanced glycolysis is associated with their maturation under aerobic conditions. J Immunol 182:7974–7981

    Article  CAS  PubMed  Google Scholar 

  24. Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201:105–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Iezzi G, Karjalainen K, Lanzavecchia A (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8:89–95

    Article  CAS  PubMed  Google Scholar 

  26. Celli S, Lemaitre F, Bousso P (2007) Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 27:625–634

    Article  CAS  PubMed  Google Scholar 

  27. Wenger RH, Stiehl DP, Camenisch G (2005) Integration of oxygen signaling at the consensus HRE. Sci STKE 2005:re12

  28. Bosco MC, Puppo M, Blengio F, Fraone T, Cappello P, Giovarelli M, Varesio L (2008) Monocytes and dendritic cells in a hypoxic environment: spotlights on chemotaxis and migration. Immunobiology 213:733–749

    Article  CAS  PubMed  Google Scholar 

  29. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055

    Article  CAS  PubMed  Google Scholar 

  30. Kopecka J, Campia I, Jacobs A, Frei AP, Ghigo D, Wollscheid B, Riganti C (2015) Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells. Oncotarget 6:6776–6793

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pierobon D, Bosco MC, Blengio F, Raggi F, Eva A, Filippi M, Musso T, Novelli F, Cappello P, Varesio L et al (2013) Chronic hypoxia reprograms human immature dendritic cells by inducing a proinflammatory phenotype and TREM-1 expression. Eur J Immunol 43:949–966

    Article  CAS  PubMed  Google Scholar 

  32. Jumper N, Paus R, Bayat A (2015) Functional histopathology of keloid disease. Histol Histopathol. 11624

  33. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG (2011) Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med 17:113–125

    Article  CAS  PubMed  Google Scholar 

  34. Mustoe TA, O’Shaughnessy K, Kloeters O (2006) Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg 117:35S–41S

    Article  CAS  PubMed  Google Scholar 

  35. van der Veer WM, Bloemen MC, Ulrich MM, Molema G, van Zuijlen PP, Middelkoop E, Niessen FB (2009) Potential cellular and molecular causes of hypertrophic scar formation. Burns 35:15–29

    Article  PubMed  Google Scholar 

  36. Jiang L, Dai Y, Cui F, Pan Y, Zhang H, Xiao J, Xiaobing FU (2014) Expression of cytokines, growth factors and apoptosis-related signal molecules in chronic pressure ulcer wounds healing. Spinal Cord 52:145–151

    Article  CAS  PubMed  Google Scholar 

  37. Sica A, Melillo G, Varesio L (2011) Hypoxia: a double-edged sword of immunity. J Mol Med (Berl) 89:657–665

    Article  CAS  Google Scholar 

  38. Bosco MC, Varesio L (2012) Dendritic cell reprogramming by the hypoxic environment. Immunobiology 217:1241–1249

    Article  CAS  PubMed  Google Scholar 

  39. Sitkovsky M, Lukashev D (2008) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5:712–721

    Article  Google Scholar 

  40. Baggiolini M, Loetscher P (2000) Chemokines in inflammation and immunity. Immunol Today 21:418–420

    Article  CAS  PubMed  Google Scholar 

  41. Wang KX, Denhardt DT (2008) Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev 19:333–345

    Article  CAS  PubMed  Google Scholar 

  42. Mori R, Shaw TJ, Martin P (2008) Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med 205:43–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang JS, Wang YH, Ling TY, Chuang SS, Johnson FE, Huang SS (2002) Synthetic TGF-beta antagonist accelerates wound healing and reduces scarring. FASEB J 16:1269–1270

    CAS  PubMed  Google Scholar 

  44. Hunger RE, Sieling PA, Ochoa MT, Sugaya M, Burdick AE, Rea TH, Brennan PJ, Belisle JT, Blauvelt A, Porcelli SA et al (2004) Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells. J Clin Invest 113:701–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schenk M, Bouchon A, Seibold F, Mueller C (2007) TREM-1—expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest 117:3097–3106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ho CC, Liao WY, Wang CY, Lu YH, Huang HY, Chen HY, Chan WK, Chen HW, Yang PC (2008) TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer. Am J Respir Crit Care Med 177:763–770

    Article  CAS  PubMed  Google Scholar 

  47. Hyder LA, Gonzalez J, Harden JL, Johnson-Huang LM, Zaba LC, Pierson KC, Eungdamrong NJ, Lentini T, Gulati N, Fuentes-Duculan J et al (2013) TREM-1 as a potential therapeutic target in psoriasis. J Invest Dermatol 133:1742–1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bleharski JR, Kiessler V, Buonsanti C, Sieling PA, Stenger S, Colonna M, Modlin RL (2003) A role for triggering receptor expressed on myeloid cells-1 in host defense during the early-induced and adaptive phases of the immune response. J Immunol 170:3812–3818

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the: Italian Association for Cancer Research IG codes 10565 (to LV), 9366 (to MG), 15257, and 121825 (funding source 5 × mille) (to FN); Italian Ministry of Health (to MCB); Fondazione Cariplo 2011-0463 (to FN); European Network for Cancer Research in Children and Adolescents (ENCCA) (to LV); Fondazione Umberto Veronesi (to LV); Fondazione Ricerca Molinette Onlus (to FN); Compagnia San Paolo (Progetti di Ricerca Ateneo) (to CC and FN); University of Torino (research funds ex 60 %) (to MG and TM); Fondazione CRT (to CC); Piedmont Foundation of Studies and Research on Burns Simone Teich Alasia (to CC). Daniele Pierobon was supported by a fellowship from the Fondazione Angela Bossolasco.

Author information

Author notes

    Authors and Affiliations

    1. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy

      Daniele Pierobon, Sergio Occhipinti, Paola Cappello, Francesco Novelli & Mirella Giovarelli

    2. CERMS, AOU Città della Salute e della Scienza di Torino, Torino, Italy

      Daniele Pierobon, Sergio Occhipinti, Paola Cappello, Francesco Novelli & Mirella Giovarelli

    3. Laboratory of Molecular Biology, G.Gaslini Institute, Genova, Italy

      Federica Raggi, Simone Pelassa, Alessandra Eva, Luigi Varesio & Maria Carla Bosco

    4. Department of Reconstructive Plastic Surgery, Burns Centre and Skin Bank, Trauma Center, Torino, Italy

      Irene Cambieri & Carlotta Castagnoli

    5. Department of Public Health and Pediatric Sciences, University of Torino, Torino, Italy

      Tiziana Musso

    6. Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, L.go G.Gaslini 5, 16147, Genova Quarto, Italy

      Luigi Varesio & Maria Carla Bosco

    Authors
    1. Daniele Pierobon
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Federica Raggi
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Irene Cambieri
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Simone Pelassa
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Sergio Occhipinti
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Paola Cappello
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Francesco Novelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Tiziana Musso
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Alessandra Eva
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Carlotta Castagnoli
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Luigi Varesio
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Mirella Giovarelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Maria Carla Bosco
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Luigi Varesio or Maria Carla Bosco.

    Ethics declarations

    Blood monocytes and naive T cells were purified from platelet-apheresis of healthy donors obtained by the Blood Transfusion Center of the Gaslini Institute (Genova, Italy) according to the Gaslini’s Ethics Committee-approved protocol. Skin biopsies were obtained from six patients with postburn active hypertrophic scars (AHT), three with decubitus ulcers (U) and four healthy individuals undergoing plastic surgery or scar correction procedures, according to a protocol approved by the CTO/Città della Salute e della Scienza Hospital Ethical Board (Torino, Italy) and in adherence with the Declaration of Helsinki Principles. Written informed consent was obtained from all subjects enrolled in the study.

    Conflicts of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Maria Carla Bosco and Mirella Giovarelli share senior authorship

    Daniele Pierobon and Federica Raggi contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 312 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Pierobon, D., Raggi, F., Cambieri, I. et al. Regulation of Langerhans cell functions in a hypoxic environment. J Mol Med 94, 943–955 (2016). https://doi.org/10.1007/s00109-016-1400-9

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-016-1400-9

    Keywords

    Search

    Navigation