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Reprogrammed fibrocytes induce a mixed Th1/Th2 cytokine response of naïve CD4+ T cells

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Abstract

Naïve CD4+ T cells develop different effector T cells and cytokine profiles after antigenic stimulation. It has been previously documented that fibrocytes function as antigen presenting cells inducing proliferation as well as Th2 cytokine response in naïve CD4+ T cells. Our group has reported that several circulating cell types recruited to the wound site can be transformed into anti-fibrotic profile cells, which subsequently induce MMP-1 stimulation in dermal fibroblasts. Here, we report how similar reprogramming pathway of fibrocytes could modify the CD4+ T cell response. Our findings confirmed that reprogrammed fibrocytes induce CD4+ T cell activation with a mixed Th1/Th2 cytokine response. Since a reciprocal positive feedback between Th2 cells and fibrocytes exist to amplify and perpetuate the pro-fibrotic stimulation in dermal fibroblasts, the novel transdifferentiation of regular mature fibrocytes into reprogrammed fibrocytes appears to be a promising strategy to reverse the Th2 cytokine overproduction, and subsequently control the local fibrogenesis.

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References

  1. Sallusto F, Lanzavecchia A (2009) Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur J Immunol 39(8):2076–2082

    Article  CAS  PubMed  Google Scholar 

  2. O’Sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML (1995) Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg 222(4):482–490

    PubMed  Google Scholar 

  3. Lyons A, Kelly JL, Rodrick ML, Mannick JA, Lederer JA (1997) Major injury induces increased production of interleukin-10 by cells of the immune system with a negative impact on resistance to infection. Ann Surg 226(4):450–458

    Article  CAS  PubMed  Google Scholar 

  4. Göebel A, Kavanagh E, Lyons A, Saporoschetz IB, Soberg C, Lederer JA, Mannick JA, Rodrick ML (2000) Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection. Ann Surg 231(2):253–261

    Article  PubMed  Google Scholar 

  5. Tredget EE, Yang L, Delehanty M, Shankowsky H, Scott PG (2006) Polarized Th2 cytokine production in patients with hypertrophic scar following thermal injury. J Interferon Cytokine Res 26(3):179–189

    Article  CAS  PubMed  Google Scholar 

  6. Bucala R, Spiegel L, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1(1):71–81

    CAS  PubMed  Google Scholar 

  7. Chesney J, Metz C, Stavitsky A, Bacher M, Bucala R (1998) Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160:419–425

    CAS  PubMed  Google Scholar 

  8. Chesney J, Bucala R (2000) Peripheral blood fibrocytes: mesenchymal precursor cells and the pathogenesis of fibrosis. Curr Rheumatol Rep 2:501–505

    Article  CAS  PubMed  Google Scholar 

  9. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE (2001) Nephrogenic fibrosing dermatopathy. Am J Dermatopathol 23:383–393

    Article  CAS  PubMed  Google Scholar 

  10. Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, Ghahary A, Tredget EE (2005) Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 13(4):398–404

    Article  PubMed  Google Scholar 

  11. Wang JF, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE (2007) Fibrocytes from burn patients regulate the activities of fibroblasts. Wound Repair Regen 15(1):113–121

    Article  PubMed  Google Scholar 

  12. Abe R, Donnelly S, Peng T, Bucala R, Metz C (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562

    CAS  PubMed  Google Scholar 

  13. Chesney J, Bacher M, Bender A, Bucala R (1997) The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA 94(12):6307–6312

    Article  CAS  PubMed  Google Scholar 

  14. Grab DJ, Salim M, Chesney J, Bucala R, Lanners HN (2002) A role for peripheral blood fibrocytes in Lyme disease? Med Hypotheses 59(1):1–10

    Article  CAS  PubMed  Google Scholar 

  15. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D (2008) Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 83(6):1323–1333

    Article  CAS  PubMed  Google Scholar 

  16. Medina A, Kilani R, Carr N, Brown E, Ghahary A (2007) Transdifferentiation of peripheral blood mononuclear cells into epithelial-like cells. Am J Pathol 171:1140–1152

    Article  CAS  PubMed  Google Scholar 

  17. Medina A, Brown E, Carr N, Ghahary A (2009) Circulating monocytes have the capacity to be transdifferentiated into keratinocyte-like cells. Wound Repair Regen 17:268–277

    Article  PubMed  Google Scholar 

  18. Medina A, Ghahary A (2010) Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts. Wound Repair Regen 18(2):245–253

    Article  PubMed  Google Scholar 

  19. Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, Tredget EE (2002) Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 82:1183–1192

    CAS  PubMed  Google Scholar 

  20. Medina A, Ghahary A (2010) Fibrocytes can be reprogrammed to promote the tissue remodeling capacity of dermal fibroblasts. Mol Cell Biochem. doi:10.1007/s11010-010-0524-4

  21. Harty M, Neff AW, King MW, Mescher AL (2003) Regeneration or scarring: an immunologic perspective. Dev Dyn 226:268–279

    Article  PubMed  Google Scholar 

  22. Bernabei P, Rigamonti L, Ariotti S, Stella M, Castagnoli C, Novelli F (1999) Functional analysis of T lymphocytes infiltrating the dermis and epidermis of post-burn hypertrophic scar tissues. Burns 25:43–48

    Article  CAS  PubMed  Google Scholar 

  23. Becker Y (2006) Molecular immunological approaches to biotherapy of human cancers—a review, hypothesis and implications. Anticancer Res 26(2A):1113–1134

    CAS  PubMed  Google Scholar 

  24. Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, Cheever AW, Pearce EJ, Wynn TA (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol 167:6533–6544

    CAS  PubMed  Google Scholar 

  25. Wynn TA (2004) Fibrotic disease and the Th1/Th2 paradigm. Nat Rev Immunol 4:583–594

    Article  CAS  PubMed  Google Scholar 

  26. Hogaboam CM, Gallinat CS, Bone-Larson C, Chensue SW, Lukacs NW, Strieter RM, Kunkel SL (1998) Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition. Am J Pathol 153:1861–1872

    CAS  PubMed  Google Scholar 

  27. Hesse M, Cheever AW, Jankovic D, Wynn TA (2000) NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease. Am J Pathol 157:945–955

    CAS  PubMed  Google Scholar 

  28. Li H, Meininger CJ, Hawker JR Jr, Haynes TE, Kepka-Lenhart D, Mistry SK, Morris SM Jr, Wu G (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280(1):E75–E82

    CAS  PubMed  Google Scholar 

  29. Blantz RC, Munger K (2002) Role of nitric oxide in inflammatory conditions. Nephron 90(4):373–378

    Article  PubMed  Google Scholar 

  30. Satriano J (2004) Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 26(4):321–329

    Article  CAS  PubMed  Google Scholar 

  31. Singh R, Pervin S, Wu G, Chaudhuri G (2001) Activation of caspase-3 activity and apoptosis in MDA-MB-468 cells by N(omega)-hydroxy-L-arginine, an inhibitor of arginase, is not solely dependent on reduction in intracellular polyamines. Carcinogenesis 22(11):1863–1869

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge M. Levings and members of her laboratory for suggestions and technical assistance in ELISA. We gratefully acknowledge M. Ochoa and E. Brown for critically reading the manuscript. We also thank the Cell Separator Unit at Vancouver General Hospital for providing blood. This work was supported by grants from the Canadian Institutes of Health Research (MOP-84276) and UBC Department of Surgery (Concept Award). Abelardo Medina holds a Canada Graduate Scholarships Doctoral Award 2006–2009 from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Burn/Wound Healing Research Laboratory, Department of Surgery, University of British Columbia, Vancouver, Canada

    Abelardo Medina & Aziz Ghahary

  2. Jack Bell Research Centre, 344A-2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Abelardo Medina & Aziz Ghahary

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  1. Abelardo Medina
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  2. Aziz Ghahary
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Correspondence to Abelardo Medina or Aziz Ghahary.

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Medina, A., Ghahary, A. Reprogrammed fibrocytes induce a mixed Th1/Th2 cytokine response of naïve CD4+ T cells. Mol Cell Biochem 346, 89–94 (2011). https://doi.org/10.1007/s11010-010-0595-2

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  • DOI: https://doi.org/10.1007/s11010-010-0595-2

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