Immunologic Research

, Volume 58, Issue 2–3, pp 186–192 | Cite as

Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation

  • S. M. Ruppert
  • T. R. Hawn
  • A. Arrigoni
  • T. N. Wight
  • P. L. Bollyky
IMMUNOLOGY AT STANFORD UNIVERSITY

Abstract

The extracellular matrix polysaccharide hyaluronan (HA) exerts size-dependent effects on leukocyte behavior. Low-molecular weight HA is abundant at sites of active tissue catabolism and promotes inflammation via effects on Toll-like receptor signaling. Conversely, high-molecular weight HA is prevalent in uninjured tissues and is anti-inflammatory. We propose that the ability of high-molecular weight but not low-molecular weight HA to cross-link CD44 functions as a novel form of pattern recognition that recognizes intact tissues and communicates “tissue integrity signals” that promote resolution of local immune responses.

Keywords

Hyaluronan Danger signals DAMP Integrity signal CD44 ECM 

Abbreviations

HMW-HA

High-molecular weight hyaluronan

LMW-HA

Low-molecular weight hyaluronan

HA

Hyaluronan

PAMPs

Pathogen-associated molecular patterns

DAMPs

Damage-associated molecular patterns

TLR

Toll-like receptor

APC

Antigen-presenting cell

DC

Dendritic cell

References

  1. 1.
    Termeer C, et al. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med. 2002;195:99–111.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Laurent TC, et al. The structure and function of hyaluronan: an overview. Immunol Cell Biol. 1996;74:A1–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Jiang D, et al. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011;91:221–64.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Jiang D, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11:1173–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002;54:195–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Teder P. Resolution of lung inflammation by CD44. Science. 2002;296:155–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Delmage JM, et al. The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci. 1986;16:303–10.PubMedGoogle Scholar
  8. 8.
    Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006;106:818–39.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Neumann A, et al. High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett. 1999;453:283–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Stern R, et al. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85:699–715.CrossRefPubMedGoogle Scholar
  11. 11.
    Forrester JV, Balazs EA. Inhibition of phagocytosis by high molecular weight hyaluronate. Immunology. 1980;40:435–46.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Suresh R, Mosser DM. Pattern recognition receptors in innate immunity, host defense, and immunopathology. Adv Physiol Educ. 2013;37:284–91.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Tian X, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;. doi:10.1038/nature12234.Google Scholar
  14. 14.
    Tsan M-F, Gao B. Heat shock proteins and immune system. J Leukoc Biol. 2009;85:905–10.CrossRefPubMedGoogle Scholar
  15. 15.
    Gasse P, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med. 2009;179:903–13.CrossRefPubMedGoogle Scholar
  16. 16.
    Campo GM, et al. Hyaluronan reduces inflammation in experimental arthritis by modulating TLR-2 and TLR-4 cartilage expression. Biochim Biophys Acta. 2011;1812:1170–81.CrossRefPubMedGoogle Scholar
  17. 17.
    Morwood SR, Nicholson LB. Modulation of the immune response by extracellular matrix proteins. Arch Immunol Ther Exp. 2006;54:367–74.CrossRefGoogle Scholar
  18. 18.
    Galeano M, et al. Systemic administration of high-molecular weight hyaluronan stimulates wound healing in genetically diabetic mice. Biochim Biophys Acta. 2011;1812:752–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Powell JD, Horton MR. Threat matrix: low-molecular-weight hyaluronan (HA) as a danger signal. Immunol Res. 2005;31:207–18.CrossRefPubMedGoogle Scholar
  20. 20.
    Hašová M, et al. Hyaluronan minimizes effects of UV irradiation on human keratinocytes. Arch Dermatol Res. 2011;303:277–84.CrossRefPubMedGoogle Scholar
  21. 21.
    Tesar BM, et al. The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transpl. 2006;6:2622–35.CrossRefGoogle Scholar
  22. 22.
    Huang PM, et al. High MW hyaluronan inhibits smoke inhalation-induced lung injury and improves survival. Respirology. 2010;15:1131–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Ye J, et al. High molecular weight hyaluronan decreases oxidative DNA damage induced by EDTA in human corneal epithelial cells. Eye (Lond). 2012;26:1012–20.CrossRefGoogle Scholar
  24. 24.
    Austin JW, et al. High molecular weight hyaluronan reduces lipopolysaccharide mediated microglial activation. J Neurochem. 2012;122:344–55.CrossRefPubMedGoogle Scholar
  25. 25.
    Ponta H, et al. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4:33–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Yamawaki H, et al. Hyaluronan receptors involved in cytokine induction in monocytes. Glycobiology. 2008;19:83–92.CrossRefPubMedGoogle Scholar
  27. 27.
    De la Motte C, et al. Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines. Am J Pathol. 2009;174:2254–64.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Campo GM, et al. Small hyaluronan oligosaccharides induce inflammation by engaging both toll-like-4 and CD44 receptors in human chondrocytes. Biochem Pharmacol. 2010;80:480–90.CrossRefPubMedGoogle Scholar
  29. 29.
    van der Windt GJW, et al. The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia. Lab Invest. 2011;91:588–97.CrossRefPubMedGoogle Scholar
  30. 30.
    McKee CM, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996;98:2403–13.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Horton MR, et al. Regulation of hyaluronan-induced chemokine gene expression by IL-10 and IFN-gamma in mouse macrophages. J Immunol. 1998;160:3023–30.PubMedGoogle Scholar
  32. 32.
    Huebener P, et al. CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response. J Immunol. 2008;180:2625–33.CrossRefPubMedGoogle Scholar
  33. 33.
    Scheibner KA, et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006;177:1272–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Zheng L, et al. Regulation of colonic epithelial repair in mice by toll-like receptors and hyaluronic acid. YGAST. 2009;137:2041–51.Google Scholar
  35. 35.
    Baaten BJG, et al. CD44 regulates survival and memory development in Th1 cells. Immunity. 2010;32:104–15.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Bollyky PL, et al. ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors. Proc Natl Acad Sci USA. 2011;108:7938–43.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Cuff CA, et al. The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation. J Clin Invest. 2001;108:1031–40.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Naor D, et al. CD44 involvement in autoimmune inflammations: the lesson to be learned from CD44-targeting by antibody or from knockout mice. Ann NY Acad Sci. 2007;1110:233–47.CrossRefPubMedGoogle Scholar
  39. 39.
    Taylor KR, et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J Biol Chem. 2007;282:18265–75.CrossRefPubMedGoogle Scholar
  40. 40.
    Muto J, et al. Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. Mol Immunol. 2009;47:449–56.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Asari A, et al. Oral administration of high molecular weight hyaluronan (900 kDa) controls immune system via Toll-like receptor 4 in the intestinal epithelium. J Biol Chem. 2010;285:24751–8.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Yasuda T. Hyaluronan inhibits Akt, leading to nuclear factor-κB down-regulation in lipopolysaccharide-stimulated U937 macrophages. J Pharmacol Sci. 2011;115:509–15.CrossRefPubMedGoogle Scholar
  43. 43.
    Liang J, et al. CD44 is a negative regulator of acute pulmonary inflammation and lipopolysaccharide-TLR signaling in mouse macrophages. J Immunol. 2007;178:2469–75.CrossRefPubMedGoogle Scholar
  44. 44.
    Kawana H, et al. CD44 suppresses TLR-mediated inflammation. J Immunol. 2008;180:4235–45.CrossRefPubMedGoogle Scholar
  45. 45.
    Sakaguchi S, et al. FOXP3 + regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500.CrossRefPubMedGoogle Scholar
  46. 46.
    Wildin RS, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18–20.CrossRefPubMedGoogle Scholar
  47. 47.
    Huter EN, et al. TGF-β-induced Foxp3 +regulatory T cells rescue scurfy mice. Eur J Immunol. 2008;38:1814–21.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Tang Q, et al. CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol. 2012;4:11–21.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Firan M, et al. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood. 2006;107:619–27.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Bollyky PL, et al. Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4 + CD25 + regulatory T cells. J Immunol. 2007;179:744–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Bollyky PL, et al. Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4 + CD25 + regulatory T cells. J Leukoc Biol. 2009;86:567–72.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Bollyky PL, et al. CD44 costimulation promotes FoxP3 + regulatory T cell persistence and function via production of IL-2, IL-10, and TGF-beta. J Immunol. 2009;183:2232–41.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Larkin J, et al. CD44 differentially activates mouse NK T cells and conventional T cells. J Immunol. 2006;177:268–79.CrossRefPubMedGoogle Scholar
  54. 54.
    Föger N, et al. CD44 supports T cell proliferation and apoptosis by apposition of protein kinases. Eur J Immunol. 2000;30:2888–99.CrossRefPubMedGoogle Scholar
  55. 55.
    Bollyky PL, et al. Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse. Cell Mol Immunol. 2010;7:211–20.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Hegde VL, et al. CD44 mobilization in allogeneic dendritic cell-T cell immunological synapse plays a key role in T cell activation. J Leukoc Biol. 2008;84:134–42.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Banerji S, et al. Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nat Struct Mol Biol. 2007;14:234–9.CrossRefPubMedGoogle Scholar
  58. 58.
    King A, et al. Interleukin-10 regulates the fetal hyaluronan-rich extracellular matrix via a STAT3-dependent mechanism. J Surg Res. 2013;184:671–7.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Mizrahy S, et al. Hyaluronan-coated nanoparticles: the influence of the molecular weight on CD44-hyaluronan interactions and on the immune response. J Control Release. 2011;156:231–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Wolny PM, et al. Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan. J Biol Chem. 2010;285:30170–80.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Fujii Y, et al. Crosslinking of CD44 on human osteoblastic cells upregulates ICAM-1 and VCAM-1. FEBS Lett. 2003;539:45–50.CrossRefPubMedGoogle Scholar
  62. 62.
    Hutás G, et al. CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis. Blood. 2008;112:4999–5006.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Marhaba R, et al. CD44v6 promotes proliferation by persisting activation of MAP kinases. Cell Signal. 2005;17:961–73.CrossRefPubMedGoogle Scholar
  64. 64.
    Sugahara KN, et al. Hyaluronan oligosaccharides induce CD44 cleavage and promote cell migration in CD44-expressing tumor cells. J Biol Chem. 2003;278:32259–65.CrossRefPubMedGoogle Scholar
  65. 65.
    Harada H, Takahashi M. CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and -2. J Biol Chem. 2007;282:5597–607.CrossRefPubMedGoogle Scholar
  66. 66.
    Bourguignon LYW, et al. CD44 interaction with Na + -H + exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J Biol Chem. 2004;279:26991–7007.CrossRefPubMedGoogle Scholar
  67. 67.
    Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the giant. J Biol Chem. 2002;277:4585–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Day AJ, De la Motte CA. Hyaluronan cross-linking: a protective mechanism in inflammation? Trends Immunol. 2005;26:637–43.CrossRefPubMedGoogle Scholar
  69. 69.
    Baranova NS, et al. The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers. J Biol Chem. 2011;286:25675–86.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Zhuo L, et al. SHAP potentiates the CD44-mediated leukocyte adhesion to the hyaluronan substratum. J Biol Chem. 2006;281:20303–14.CrossRefPubMedGoogle Scholar
  71. 71.
    Lesley J, et al. TSG-6 modulates the interaction between hyaluronan and cell surface CD44. J Biol Chem. 2004;279:25745–54.CrossRefPubMedGoogle Scholar
  72. 72.
    Tan KT, et al. Characterization of hyaluronan and TSG-6 in skin scarring: differential distribution in keloid scars, normal scars and unscarred skin. J Eur Acad Dermatol Venereol. 2011;25:317–27.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Kvezereli M, et al. TSG-6 protein expression in the pancreatic islets of NOD mice. J Mol Histol. 2008;39:585–93.CrossRefPubMedGoogle Scholar
  74. 74.
    Bárdos T, et al. Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis. Am J Pathol. 2001;159:1711–21.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Kota DJ, et al. TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. Diabetes. 2013;62:2048–58.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Evanko SP, et al. Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol. 2012;31:90–100.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Liu Y, et al. High-molecular-weight hyaluronan—a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats. Crit Care. 2008;12:R102.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 2012;20:317–31.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • S. M. Ruppert
    • 1
  • T. R. Hawn
    • 2
  • A. Arrigoni
    • 1
  • T. N. Wight
    • 3
  • P. L. Bollyky
    • 1
  1. 1.Division of Infectious DiseasesStanford University School of MedicineStanfordUSA
  2. 2.Division of Allergy and Infectious DiseasesUniversity of Washington Medical CenterSeattleUSA
  3. 3.Matrix Biology DivisionBenaroya Research InstituteSeattleUSA

Personalised recommendations