Skip to main content

Advertisement

SpringerLink
Log in

Intermediate Molecular Mass Hyaluronan and CD44 Receptor Interactions Enhance Neutrophil Phagocytosis and IL-8 Production via p38- and ERK1/2-MAPK Signalling Pathways

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

CD44 is a common leukocyte adhesion molecule expressed on the surface of various cells. Hyaluronan (HA), the natural ligand of CD44, is a simple repeated disaccharide with variable molecular mass that is widely distributed on cell surfaces and the connective tissue matrix. The binding of small molecular mass HA (SMM-HA, MW < 80 kDa) to CD44 on immune-related cells elicits cell proliferation, differentiation, and cytokine production. However, the effects and molecular basis of intermediate molecular mass HA (IMM-HA, MW ≈ 500 kDa)-CD44 interactions on polymorphonuclear neutrophil (PMN) functions have not been elucidated. We hypothesised that IMM-HA would potentiate immune functions as well as SMM-HA. In the present study, we demonstrated IMM-HA and CD44 interactions enhanced normal PMN phagocytosis and IL-8 production compared to those with LPS or anti-CD45 treatment via F-actin cytoskeleton polymerization and subsequent ERK1/2- and p38-MAPK phosphorylation. Antibody-based inhibition of CD44 did not affect PMN function; however, F-actin aggregation was induced without MAPK phosphorylation. Enhanced PMN function via IMM-HA was determined to be CD44-dependent since this effect was abolished in DMSO-induced CD44(−) PMN-like cells obtained from HL-60 cells. In conclusion, we demonstrated that IMM-HA and CD44 interactions on PMNs potently elicit F-actin cytoskeleton polymerization and p38- and ERK1/2-MAPK phosphorylation to enhance PMN function.

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. Lesley, J., R. Hyman, and P.W. Kincade. 1993. CD44 and its interaction with extracellular matrix. Advances in Immunology 54: 271–335.

    Article  CAS  PubMed  Google Scholar 

  2. Lesley, J., R. Hyman, N. English, J.B. Catterall, and G.A. Turner. 1997. CD44 in inflammation and metastasis. Glycoconjugate Journal 14: 611–622.

    Article  CAS  PubMed  Google Scholar 

  3. Siegelman, M.H., H.C. DeGrendele, and P. Estess. 1999. Activation and interaction of CD44 and hyaluronan in immunological systems. Journal of Leukocyte Biology 66: 315–321.

    CAS  PubMed  Google Scholar 

  4. Johnson, P., and B. Ruffell. CD44 and its role in inflammation and inflammatory diseases. Inflammation & Allergy Drug Targets 200 (8): 208–220.

  5. Bourguignon, L.Y. 2008. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Seminars in Cancer Biology 18: 251–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Heldin, P., E. Karousou, B. Bernert, H. Porsch, K. Nishitsuka, and S.S. Skandalis. 2008. Importance of hyaluronan-CD44 interactions in inflammation and tumorigenesis. Connective Tissue Research 49: 215–218.

    Article  CAS  PubMed  Google Scholar 

  7. Bourguignon, L.Y., M. Shiina, and J.J. Li. 2014. Hyaluronan-CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. Advances in Cancer Research 123: 255–275.

    Article  CAS  PubMed  Google Scholar 

  8. Jordan, A.R., R.R. Racine, M.J. Hennig, and V.B. Lokeshwar. 2015. The role of CD44 in disease pathophysiology and targeted treatment. Frontiers in Immunology (6) Article 182.

  9. Laurent, T.C., and J.R. Fraser. 1992. Hyaluronan. The FASEB Journal 6: 2397–2404.

    CAS  PubMed  Google Scholar 

  10. Fraser, J.R., T.C. Laurent, and U.B. Laurent. 1997. Hyaluronan: Its nature, distribution, functions and turnover. Journal of Internal Medicine 242: 27–33.

    Article  CAS  PubMed  Google Scholar 

  11. Lee, J.Y., and A.P. Spicer. 2000. Hyaluronan: a multifunctional, megaDalton, stealth molecule. Current Opinion in Cell Biology 12: 581–586.

    Article  CAS  PubMed  Google Scholar 

  12. Toole, B.P. 2004. Hyaluronan: from extracellular glue to pericellular cue. Nature Reviews. Cancer 4: 528–539.

    Article  CAS  PubMed  Google Scholar 

  13. Misra, S., V.C. Hascall, R.R. Markwald, and S. Ghatak. 2015. Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Frontiers in Immunology 6 Article 201.

  14. Yamawaki, H., S. Hirohata, T. Miyoshi, K. Takahashi, H. Ogawa, R. Shinohata, K. Demircan, S. Kusachi, K. Yamamoto, and Y. Ninomiya. 2009. Hyaluronan receptors involved in cytokine induction in monocytes. Glycobiology 19: 83–92.

    Article  CAS  PubMed  Google Scholar 

  15. Jiang, D., J. Liang, and P.W. Noble. 2011. Hyaluronan as an immune regulator in human diseases. Physiological Reviews 91: 221–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chang, E.-J., H.J. Kim, J. Ha, H.J. Kim, J. Ryu, K.-H. Park, U.-H. Kim, Z.H. Lee, H.-M. Kim, D.E. Fisher, and H.-H. Kim. 2007. Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4. Journal of Cell Science 120: 166–176.

    Article  CAS  PubMed  Google Scholar 

  17. Noble, P.W. 2002. Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biology 21: 25–29.

    Article  CAS  PubMed  Google Scholar 

  18. Cowman, M.K., H.G. Lee, K.L. Schwertfeger, J.B. McCarthy, and E.A. Turley. 2015. The content and size of hyaluronan in biological fluids and tissues. Frontiers in Immunology 6 Article 261.

  19. Wang, J.Y., and M.H. Roehrl. 2002. Glycosaminoglycans are a potential cause of rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America 99: 14362–14367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gyorgy, B., L. Tothfalusi, G. Nagy, M. Pasztoi, P. Geher, Z. Lorinc, A. Polgar, B. Rojkovich, I. Ujfalussy, G. Poor, P. Pocza, Z. Wiener, P. Misjak, A. Koncz, A. Falus, and E.I. Buzas. 2008. Natural autoantibodies reactive with glycosaminoglycans in rheumatoid arthritis. Arthritis Research & Therapy 10: R110.

    Article  Google Scholar 

  21. Brawer, A.E., and N. Goel. 2016. The onset of rheumatoid arthritis following trauma. Open Access Rheumatology: Research and Reviews 8: 77–80.

    Article  Google Scholar 

  22. Kerje, S., U. Hellman, L. Do, G. Larsson, O. Kampe, A. Engstrom-Laurent, and U. Lindqvist. 2016. Is low molecular weight hyaluronan an early indicator of disease in avian systemic sclerosis? Connective Tissue Research 57: 337–346.

    Article  CAS  PubMed  Google Scholar 

  23. Lauer, M.E., A.K. Majors, S. Comhair, L.M. Ruple, B. Matuska, A. Subramanian, C. Farver, R. Dworski, D. Grandon, D. Laskowski, R.A. Dweik, S.C. Erzurum, V.C. Hascall, and M.A. Aronica. 2015. Hyaluronan and its heavy chain modification in asthma severity and experimental asthma exacerbation. The Journal of Biological Chemistry 290: 23124–23134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oh, J.H., Y.K. Kim, J.Y. Jung, J.E. Shin, and J.H. Chung. 2011. Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo. Experimental Dermatology 20: 454–456.

    Article  PubMed  Google Scholar 

  25. Tashiro, K., M. Shishido, K. Fujimoto, Y. Hirota, K. Yo, T. Gomi, and Y. Tanaka. 2014. Age-related disruption of autophagy in dermal fibroblasts modulates extracellular matrix components. Biochemical and Biophysical Research Communications 443: 167–172.

    Article  CAS  PubMed  Google Scholar 

  26. Lee, D.H., J.H. Oh, and J.H. Chung. 2016. Glycosaminoglycan and proteoglycan in skin aging. Journal of Dermatological Science 83: 174–181.

    Article  CAS  PubMed  Google Scholar 

  27. Tammi, M., P.O. Seppala, A. Lehtonen, and M. Mottonen. 1978. Connective tissue components in normal and atherosclerotic human coronary arteries. Atherosclerosis 29: 191–194.

    Article  CAS  PubMed  Google Scholar 

  28. Yla-Herttuala, S., H. Sumuvuori, K. Karkola, M. Mottonen, and T. Nikkari. 1986. Glycosaminoglycans in normal and atherosclerotic human coronary arteries. Laboratory Investigation 54: 402–407.

    CAS  PubMed  Google Scholar 

  29. Hauert, A.B., S. Martinelli, C. Marone, and V. Niggli. 2002. Differentiated HL-60 cells are valid model system for the analysis of human neutrophil migration and chemotaxis. The International Journal of Biochemistry & Cell Biology 34: 838–854.

    Article  CAS  Google Scholar 

  30. Shalaby, M.R., B.B. Aggarwal, E. Rinderknecht, L.P. Svedersky, B.S. Finkle, and M.A. Palladino Jr. 1985. Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. Journal of Immunology 135: 2069–2073.

    CAS  Google Scholar 

  31. Spertini, F., A.V. Wang, T. Chatila, and R.S. Geha. 1994. Engagement of the common leukocyte antigen CD45 induces homotypic adhesion of activated human T cells. Journal of Immunology 153: 1593–1602.

    CAS  Google Scholar 

  32. Yu, C.L., H.S. Yu, K.H. Sun, S.C. Hsieh, and C.Y. Tsai. 2002. Anti-CD45 isoform antibodies enhance phagocytosis and gene expression of IL-8 and TNF-alpha in human neutrophils by differential suppression on protein tyrosine phosphorylation and p56lck tyrosine kinase. Clinical and Experimental Immunology 129: 78–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. May, R.C., and L.M. Machesky. 2001. Phagocytosis and the actin cytoskeleton. Journal of Cell Science 114: 1061–1077.

    CAS  PubMed  Google Scholar 

  34. Groves, E., A.E. Dart, V. Covarelli, and E. Caron. 2008. Molecular mechanisms of phagocytic uptake in mammalian cells. Cellular and Molecular Life Sciences 65: 1957–1976.

    Article  CAS  PubMed  Google Scholar 

  35. Underhill, D.M., and H.S. Goodridge. 2012. Information processing during phagocytosis. Nature Reviews. Immunology 12: 492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, K.J., S.C. Siao, C.H. Wu, C.Y. Shen, T.H. Wu, C.Y. Tsai, S.C. Hsieh, and C.L. Yu. 2013. EGF receptor-dependent mechanism may be involved in the Tamm-Horsfall glycoprotein-enhanced PMN phagocytosis via activating Rho family and MAPK signaling pathway. Molecules 19: 1328–1343.

    Article  Google Scholar 

  37. Sherman, L., J. Sleeman, P. Herrlich, and H. Ponta. 1994. Hyaluronate receptors: Key players in growth, differentiation, migration and tumor progression. Current Opinion in Cell Biology 6: 726–733.

    Article  CAS  PubMed  Google Scholar 

  38. Naor, D., R.V. Sionov, and D. Ish-Shalom. 1997. CD44: Structure, function, and association with the malignant process. Advances in Cancer Research 71: 241–319.

    Article  CAS  PubMed  Google Scholar 

  39. Bourrguignon, L.Y., N. Lida, C.F. Welsh, D. ZHu, A. Krongrad, and D. Pasguale. 1995. Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction, cell adhesion, and tumor metastasis. Journal of Neuro-Oncology 26: 201–208.

    Article  CAS  PubMed  Google Scholar 

  40. Wittig, B., S. Seiter, N. Foger, C. Schwarzler, U. Gunthert, and M. Zoller. 1997. Functional activity of murine CD44 variant isoforms in allergic and delayed type hypersensitivity. Immunology Letters 57: 217–223.

    Article  CAS  PubMed  Google Scholar 

  41. Witting, B.M., A. Stallmach, M. Zeitz, and U. Gunthert. 2002. Functional involvement of CD44 variant 7 in gut immune response. Pathology 70: 184–189.

    Google Scholar 

  42. Hoffmann, U., K. Heilmann, C. Hayford, A. Stallmach, U. Wahnschaffe, M. Zeitz, U. Gunthert, and B.M. Wittig. 2007. CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria. Cell Death and Differentiation 14: 1542–1551.

    Article  CAS  PubMed  Google Scholar 

  43. Slevin, M., J. Krupinski, J. Gaffney, S. Matou, D. West, H. Delisser, R.C. Savani, and S. Kumar. 2007. Hyaluronan-mediated angiogenesis in vascular disease: Uncovering RHAMM and CD44 receptor signaling pathways. Matrix Biology 26: 58–68.

    Article  CAS  PubMed  Google Scholar 

  44. Heldin, P., K. Basu, B. Olofsson, H. Porsch, I. Kozlova, and K. Kahata. 2013. Deregulation of hyaluronan synthesis, degradation and binding promotes breast cancer. Journal of Biochemistry 154: 395–408.

    Article  CAS  PubMed  Google Scholar 

  45. Termeer, C.C., J. Hennies, U. Voith, T. Ahrens, J.M. Weiss, P. Prehm, and J.C. Simon. 2000. Oligosaccharides of hyaluronan are potent activators of dendritic cells. Journal of Immunology 165: 1863–1870.

    Article  CAS  Google Scholar 

  46. Termeer, C., F. Benedix, J. Sleeman, C. Fieber, U. Voith, T. Ahrens, K. Miyake, M. Freudenberg, C. Galanos, and J.C. Simon. 2002. Oligosaccharides of hyaluronan activate dendritic cell via Toll-like receptor 4. The Journal of Experimental Medicine 195: 99–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Orian-Rousseau, V., and M. Schmitt. 2015. CD44 regulates Wnt signaling at the level of LRP6. Molecular & Cellular Oncology 2: e995046.

    Article  Google Scholar 

  48. Lee, Y.-T., H.-J. Shao, J.-H. Wang, H.-C. Liu, S.-M. Hou, and T.-H. Young. 2010. Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro. Journal of Orthopaedic Research 28: 492–496.

    Article  CAS  PubMed  Google Scholar 

  49. Hiraoka, N., K. Takahashi, Y. Arai, K. Sakao, O. Mazda, T. Kishida, K. Honjo, S. Tanaka, and T. Kubo. 2011. Intra-articular injection of hyaluronan restores the aberrant expression of matrix metalloproteinase-13 in osteoarthritic subchondral bone. Journal of Orthopaedic Research 29: 354–360.

    Article  CAS  PubMed  Google Scholar 

  50. Bauer, C., E. Niculescu-Morzsa, V. Jeyakumar, D. Kern, S.S. Spath, and S. Nehrer. 2016. Chondroprotective effect of high molecular-weight hyaluronic acid on osteoarthritic chondrocytes in a co-cultivation inflammation model with M1 macrophages. Journal of Inflammation 13: 31–39.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Altman, R.D., A. Manjoo, A. Fierlinger, F. Niazi, and M. Nicholls. 2015. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: A systemic review. BMC Musculoskeletal Disorders 1: 321–330.

    Article  Google Scholar 

  52. Brzusek, D., and D. Petron. 2008. Treating knee osteoarthritis with intra-articular hyaluronans. Current Medical Research and Opinion 24: 3307–3322.

    Article  CAS  PubMed  Google Scholar 

  53. Puttick, M.P., J.P. Wade, A. Chalmers, D.G. Connell, and K.K. Rangno. 1995. Acute local reactions after intraarticular hylan for osteoarthritis of the knee. The Journal of Rheumatology 22: 1311–1314.

    CAS  PubMed  Google Scholar 

  54. Refsnes, M., T. Skuland, P.E. Schwarze, J. Ovrevik, and M. Lag. 2008. Fluoride-induced IL-8 release in human epithelial lung cells: Relationship to EGF-receptor-, SRC- and MAP-kinase activation. Toxicology and Applied Pharmacology 227: 56–67.

    Article  CAS  PubMed  Google Scholar 

  55. Zhang, Y., L. Wang, M. Zhang, M. Jin, C. Bai, and X. Wang. 2012. Potential mechanism of interleukin-8 production from lung cancer cells: An involvement of EGF-EGFR-PI3K-Akt-Erk pathway. Journal of Cellular Physiology 227: 35–43.

    Article  CAS  PubMed  Google Scholar 

  56. Shi, L., L. Wang, B. Wang, S.M. Cretoiu, Q. Wang, X. Wang, and C. Chen. 2014. Regulatory mechanisms of betacellulin in CXCL8 production from lung cancer cells. Journal of Translational Medicine 12: 70. doi:10.1186/1479-5876-12-70.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hanabayashi, M., N. Takahashi, Y. Sobue, S. Hirabara, N. Ishiguro, and T. Kojima. 2016. Hyaluronan oligosaccharides induce MMP-1 and -3 via transcriptional activation of NF-κB and p38 MAPK in rheumatoid synovial fibroblasts. PLoS One 11: e0161875.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are indebted to the Immunology Research Center and Second Core Laboratory, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.

Author information

Authors and Affiliations

  1. Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7 Chung-San South Road, Taipei, 10002, Taiwan

    Cheng-Hsun Lu, Chieh-Yu Shen, Cheng-Han Wu & Yu-Min Kuo

  2. Department of Internal Medicine, National Taiwan University Hospital-Yunlin Branch, No. 95 Xuefu Rd, Huwei Township, Yunlin County, 632, Taiwan

    Cheng-Hsun Lu & Ting-Syuan Lin

  3. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No. 7, Chung-San South Road, Taipei, 10002, Taiwan

    Chia-Huei Lin, Ko-Jen Li, Chieh-Yu Shen, Cheng-Han Wu, Yu-Min Kuo, Chia-Li Yu & Song-Chou Hsieh

  4. Institute of Molecular Medicine, National Taiwan University College of Medicine, No. 7 Chung-San South Road, Taipei, 10002, Taiwan

    Chia-Li Yu

Authors
  1. Cheng-Hsun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chia-Huei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ko-Jen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chieh-Yu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng-Han Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Min Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ting-Syuan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chia-Li Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Song-Chou Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors’ Contributions

Conceived and designed the experiments: YCY, HSC. Performed the experiments and analysed data: LuCH, LinCH. Contributed reagents/materials/analysis: LKJ, SCY, WCH, KYM. Wrote the paper: LuCH, YCY, HSC, LKJ

All authors read and approved the final manuscript.

Corresponding author

Correspondence to Song-Chou Hsieh.

Ethics declarations

Funding

This study was supported by a grant from the National Sciences Council (NSC99-2628-B-002-020-MY3, NSC100-2314-B-002-144).

Competing Interests

The authors declare that they have no competing interests.

Consent for Publication

Not applicable

Ethics Approval and Consent to Participate

Healthy volunteers were recruited according to a protocol that was approved by the Institutional Review Board and Ethical Committee of National Taiwan University Hospital, Taipei, Taiwan. Each participant provided signed informed consent.

Additional information

Cheng-Hsun Lu and Chia-Huei Lin contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, CH., Lin, CH., Li, KJ. et al. Intermediate Molecular Mass Hyaluronan and CD44 Receptor Interactions Enhance Neutrophil Phagocytosis and IL-8 Production via p38- and ERK1/2-MAPK Signalling Pathways. Inflammation 40, 1782–1793 (2017). https://doi.org/10.1007/s10753-017-0622-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-017-0622-5

KEY WORDS

Search

Navigation