Skip to main content
SpringerLink
Log in

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

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

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.

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

Similar content being viewed by others

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. Termeer C, et al. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med. 2002;195:99–111.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Laurent TC, et al. The structure and function of hyaluronan: an overview. Immunol Cell Biol. 1996;74:A1–7.

    Article  CAS  PubMed  Google Scholar 

  3. Jiang D, et al. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011;91:221–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Jiang D, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11:1173–9.

    Article  CAS  PubMed  Google Scholar 

  5. Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002;54:195–9.

    Article  CAS  PubMed  Google Scholar 

  6. Teder P. Resolution of lung inflammation by CD44. Science. 2002;296:155–8.

    Article  CAS  PubMed  Google Scholar 

  7. Delmage JM, et al. The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci. 1986;16:303–10.

    CAS  PubMed  Google Scholar 

  8. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006;106:818–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  10. Stern R, et al. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85:699–715.

    Article  CAS  PubMed  Google Scholar 

  11. Forrester JV, Balazs EA. Inhibition of phagocytosis by high molecular weight hyaluronate. Immunology. 1980;40:435–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Suresh R, Mosser DM. Pattern recognition receptors in innate immunity, host defense, and immunopathology. Adv Physiol Educ. 2013;37:284–91.

    Article  PubMed Central  PubMed  Google Scholar 

  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. Tsan M-F, Gao B. Heat shock proteins and immune system. J Leukoc Biol. 2009;85:905–10.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  17. Morwood SR, Nicholson LB. Modulation of the immune response by extracellular matrix proteins. Arch Immunol Ther Exp. 2006;54:367–74.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Powell JD, Horton MR. Threat matrix: low-molecular-weight hyaluronan (HA) as a danger signal. Immunol Res. 2005;31:207–18.

    Article  CAS  PubMed  Google Scholar 

  20. Hašová M, et al. Hyaluronan minimizes effects of UV irradiation on human keratinocytes. Arch Dermatol Res. 2011;303:277–84.

    Article  PubMed  Google Scholar 

  21. Tesar BM, et al. The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transpl. 2006;6:2622–35.

    Article  CAS  Google Scholar 

  22. Huang PM, et al. High MW hyaluronan inhibits smoke inhalation-induced lung injury and improves survival. Respirology. 2010;15:1131–9.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  24. Austin JW, et al. High molecular weight hyaluronan reduces lipopolysaccharide mediated microglial activation. J Neurochem. 2012;122:344–55.

    Article  CAS  PubMed  Google Scholar 

  25. Ponta H, et al. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4:33–45.

    Article  CAS  PubMed  Google Scholar 

  26. Yamawaki H, et al. Hyaluronan receptors involved in cytokine induction in monocytes. Glycobiology. 2008;19:83–92.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  33. Scheibner KA, et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006;177:1272–81.

    Article  CAS  PubMed  Google Scholar 

  34. Zheng L, et al. Regulation of colonic epithelial repair in mice by toll-like receptors and hyaluronic acid. YGAST. 2009;137:2041–51.

    CAS  Google Scholar 

  35. Baaten BJG, et al. CD44 regulates survival and memory development in Th1 cells. Immunity. 2010;32:104–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. Kawana H, et al. CD44 suppresses TLR-mediated inflammation. J Immunol. 2008;180:4235–45.

    Article  CAS  PubMed  Google Scholar 

  45. Sakaguchi S, et al. FOXP3 + regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  47. Huter EN, et al. TGF-β-induced Foxp3 +regulatory T cells rescue scurfy mice. Eur J Immunol. 2008;38:1814–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Tang Q, et al. CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol. 2012;4:11–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Firan M, et al. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood. 2006;107:619–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Larkin J, et al. CD44 differentially activates mouse NK T cells and conventional T cells. J Immunol. 2006;177:268–79.

    Article  CAS  PubMed  Google Scholar 

  54. Föger N, et al. CD44 supports T cell proliferation and apoptosis by apposition of protein kinases. Eur J Immunol. 2000;30:2888–99.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Fujii Y, et al. Crosslinking of CD44 on human osteoblastic cells upregulates ICAM-1 and VCAM-1. FEBS Lett. 2003;539:45–50.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Marhaba R, et al. CD44v6 promotes proliferation by persisting activation of MAP kinases. Cell Signal. 2005;17:961–73.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  67. Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the giant. J Biol Chem. 2002;277:4585–8.

    Article  CAS  PubMed  Google Scholar 

  68. Day AJ, De la Motte CA. Hyaluronan cross-linking: a protective mechanism in inflammation? Trends Immunol. 2005;26:637–43.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Zhuo L, et al. SHAP potentiates the CD44-mediated leukocyte adhesion to the hyaluronan substratum. J Biol Chem. 2006;281:20303–14.

    Article  CAS  PubMed  Google Scholar 

  71. Lesley J, et al. TSG-6 modulates the interaction between hyaluronan and cell surface CD44. J Biol Chem. 2004;279:25745–54.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Kvezereli M, et al. TSG-6 protein expression in the pancreatic islets of NOD mice. J Mol Histol. 2008;39:585–93.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Evanko SP, et al. Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol. 2012;31:90–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institutes of Health grants T32 AI07290 (to SMR); R01 DK096087-01, R01 HL113294-01A1, and U01 AI101984 (to PLB); and HL018645 and a BIRT supplement AR037296 (to TNW). The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Infectious Diseases, Stanford University School of Medicine, 300 Pasteur Drive, Rm. L-133, Stanford, CA, 94305-5107, USA

    S. M. Ruppert, A. Arrigoni & P. L. Bollyky

  2. Division of Allergy and Infectious Diseases, University of Washington Medical Center, 1959 NE Pacific Ave, Seattle, WA, 98195, USA

    T. R. Hawn

  3. Matrix Biology Division, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA

    T. N. Wight

Authors
  1. S. M. Ruppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. R. Hawn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Arrigoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. N. Wight
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. L. Bollyky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. L. Bollyky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruppert, S.M., Hawn, T.R., Arrigoni, A. et al. Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res 58, 186–192 (2014). https://doi.org/10.1007/s12026-014-8495-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8495-2

Keywords

Search

Navigation