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Role of Complement on Broken Surfaces After Trauma

  • Markus Huber-Lang
  • Anita Ignatius
  • Rolf E. Brenner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 865)

Abstract

Activation of both the complement and coagulation cascade after trauma and subsequent local and systemic inflammatory response represent a major scientific and clinical problem. After severe tissue injury and bone fracture, exposure of innate immunity to damaged cells and molecular debris is considered a main trigger of the posttraumatic danger response. However, the effects of cellular fragments (e.g., histones) on complement activation remain enigmatic. Furthermore, direct effects of “broken” bone and cartilage surfaces on the fluid phase response of complement and its interaction with key cells of connective tissues are still unknown. Here, we summarize data suggesting direct and indirect complement activation by extracellular and cellular danger associated molecular patterns. In addition, key complement components and the corresponding receptors (such as C3aR, C5aR) have been detected on “exposed surfaces” of the damaged regions. On a cellular level, multiple effects of complement activation products on osteoblasts, osteoclasts, chondrocytes and mesenchymal stem cells have been found.

In conclusion, the complement system may be activated by trauma-altered surfaces and is crucially involved in connective tissue healing and posttraumatic systemic inflammatory response.

Keywords

Mesenchymal stem cells Complement Trauma Broken surfaces 

Notes

Acknowledgments

The cited author’s own work was funded in part by the State of Baden-Württemberg (Perspektivförderung), the DFG Clinical Research Unit KFO200 TP2 and TP4, and the SFB1149.

References

  1. 1.
    Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med. 2006;12:682–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Zhao C, Itagaki K, Gupta A, Odom S, Sandler N, Hauser CJ. Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses. J Trauma Acute Care Surg. 2014;76:1222–7.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Brinkmann CR, Jensen L, Dagnaes-Hansen F, Holm IE, Endo Y, Fujita T, Thiel S, Jensenius JC, Degn SE. Mitochondria and the lectin pathway of complement. J Biol Chem. 2013;288:8016–27.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Huber-Lang M, Barratt-Due A, Pischke SE, Sandanger O, Nilsson PH, Nunn MA, Denk S, Gaus W, Espevik T, Mollnes TE. Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. J Immunol. 2014;192:5324–31.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Song WC. Crosstalk between complement and toll-like receptors. Toxicol Pathol. 2012;40:174–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Johansson PI, Windelov NA, Rasmussen LS, Sorensen AM, Ostrowski SR. Blood levels of histone-complexed DNA fragments are associated with coagulopathy, inflammation and endothelial damage early after trauma. J Emerg Trauma Shock. 2013;6:171–5.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, Bruckner U, Stahl GL, Blom AM, Perl M, Gebhard F, Huber-Lang M. Early complementopathy after multiple injuries in humans. Shock. 2012;37:348–54.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Kanse SM, Gallenmueller A, Zeerleder S, Stephan F, Rannou O, Denk S, Etscheid M, Lochnit G, Krueger M, Huber-Lang M. Factor VII-activating protease is activated in multiple trauma patients and generates anaphylatoxin C5a. J Immunol. 2012;188:2858–65.CrossRefPubMedGoogle Scholar
  10. 10.
    Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148:293–300.CrossRefPubMedGoogle Scholar
  11. 11.
    Bohlson SS, O’Conner SD, Hulsebus HJ, Ho MM, Fraser DA. Complement, c1q, and c1q-related molecules regulate macrophage polarization. Front Immunol. 2014;5:402.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Diepenhorst GM, van Gulik TM, Hack CE. Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. Ann Surg. 2009;249:889–99.CrossRefPubMedGoogle Scholar
  13. 13.
    Bless NM, Warner RL, Padgaonkar VA, Lentsch AB, Czermak BJ, Schmal H, Friedl HP, Ward PA. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion. Am J Physiol. 1999;276:L57–63.PubMedGoogle Scholar
  14. 14.
    Duehrkop C, Banz Y, Spirig R, Miescher S, Nolte MW, Spycher M, Smith RA, Sacks SH, Rieben R. C1 esterase inhibitor reduces lower extremity ischemia/reperfusion injury and associated lung damage. PLoS One. 2013;8, e72059.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Lindsay TF, Hill J, Ortiz F, Rudolph A, Valeri CR, Hechtman HB, Moore Jr FD. Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemia-reperfusion. Ann Surg. 1992;216:677–83.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Woodruff TM, Arumugam TV, Shiels IA, Reid RC, Fairlie DP, Taylor SM. Protective effects of a potent C5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats. J Surg Res. 2004;116:81–90.CrossRefPubMedGoogle Scholar
  17. 17.
    Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12:211.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006;20:739–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Furman BD, Olson SA, Guilak F. The development of posttraumatic arthritis after articular fracture. J Orthop Trauma. 2006;20:719–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Brophy RH, Martinez M, Borrelli Jr J, Silva MJ. Effect of combined traumatic impact and radial transection of medial meniscus on knee articular cartilage in a rabbit in vivo model. Arthroscopy. 2012;28:1490–6.CrossRefPubMedGoogle Scholar
  21. 21.
    McKinley TO, Borrelli Jr J, D’Lima DD, Furman BD, Giannoudis PV. Basic science of intra-articular fractures and posttraumatic osteoarthritis. J Orthop Trauma. 2010;24:567–70.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Honkonen SE. Degenerative arthritis after tibial plateau fractures. J Orthop Trauma. 1995;9:273–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Volpin G, Dowd GS, Stein H, Bentley G. Degenerative arthritis after intra-articular fractures of the knee. Long-term results. J Bone Joint Surg Br. 1990;72:634–8.PubMedGoogle Scholar
  24. 24.
    Jansen NW, Roosendaal G, Bijlsma JW, Degroot J, Lafeber FP. Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study. Arthritis Rheum. 2007;56:199–207.CrossRefPubMedGoogle Scholar
  25. 25.
    van Meegeren ME, Roosendaal G, Barten-van Rijbroek AD, Schutgens RE, Lafeber FP, Mastbergen SC. Coagulation aggravates blood-induced joint damage in dogs. Arthritis Rheum. 2012;64:3231–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51:249–57.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Orlowsky EW, Kraus VB. The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive. J Rheumatol. 2015;2(3):363–71.CrossRefGoogle Scholar
  28. 28.
    Schaefer L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem. 2014;289:35237–45.CrossRefPubMedGoogle Scholar
  29. 29.
    Backus JD, Furman BD, Swimmer T, Kent CL, McNulty AL, Defrate LE, Guilak F, Olson SA. Cartilage viability and catabolism in the intact porcine knee following transarticular impact loading with and without articular fracture. J Orthop Res. 2011;29:501–10.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Lewis JL, Deloria LB, Oyen-Tiesma M, Thompson Jr RC, Ericson M, Oegema Jr TR. Cell death after cartilage impact occurs around matrix cracks. J Orthop Res. 2003;21:881–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Sjoberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol. 2009;30:83–90.CrossRefPubMedGoogle Scholar
  32. 32.
    Heinegard D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol. 2011;7:50–6.CrossRefPubMedGoogle Scholar
  33. 33.
    John T, Stahel PF, Morgan SJ, Schulze-Tanzil G. Impact of the complement cascade on posttraumatic cartilage inflammation and degradation. Histol Histopathol. 2007;22:781–90.PubMedGoogle Scholar
  34. 34.
    Bradley K, North J, Saunders D, Schwaeble W, Jeziorska M, Woolley DE, Whaley K. Synthesis of classical pathway complement components by chondrocytes. Immunology. 1996;88:648–56.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Schulze-Tanzil G, Kohl B, El SK, Arens S, Ertel W, Stolzel K, John T. Anaphylatoxin receptors and complement regulatory proteins in human articular and non-articular chondrocytes: interrelation with cytokines. Cell Tissue Res. 2012;350:465–75.CrossRefPubMedGoogle Scholar
  36. 36.
    Onuma H, Masuko-Hongo K, Yuan G, Sakata M, Nakamura H, Kato T, Aoki H, Nishioka K. Expression of the anaphylatoxin receptor C5aR (CD88) by human articular chondrocytes. Rheumatol Int. 2002;22:52–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen DM, Crish JF, Bebek G, Ritter SY, Lindstrom TM, Hwang I, Wong HH, Punzi L, Encarnacion A, Shamloo M, Goodman SB, Wyss-Coray T, Goldring SR, Banda NK, Thurman JM, Gobezie R, Crow MK, Holers VM, Lee DM, Robinson WH. Identification of a central role for complement in osteoarthritis. Nat Med. 2011;17:1674–9.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Happonen KE, Heinegard D, Saxne T, Blom AM. Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases. Immunobiology. 2012;217:1088–96.CrossRefPubMedGoogle Scholar
  39. 39.
    Sjoberg AP, Manderson GA, Morgelin M, Day AJ, Heinegard D, Blom AM. Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation. Mol Immunol. 2009;46:830–9.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Krumdieck R, Hook M, Rosenberg LC, Volanakis JE. The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex. J Immunol. 1992;149:3695–701.PubMedGoogle Scholar
  41. 41.
    Bing DH, Almeda S, Isliker H, Lahav J, Hynes RO. Fibronectin binds to the C1q component of complement. Proc Natl Acad Sci U S A. 1982;79:4198–201.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Almeda S, Rosenberg RD, Bing DH. The binding properties of human complement component C1q. Interaction with mucopolysaccharides. J Biol Chem. 1983;258:785–91.PubMedGoogle Scholar
  43. 43.
    Clark SJ, Bishop PN, Day AJ. The proteoglycan glycomatrix: a sugar microenvironment essential for complement regulation. Front Immunol. 2013;4:412.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Kalchishkova N, Furst CM, Heinegard D, Blom AM. NC4 Domain of cartilage-specific collagen IX inhibits complement directly due to attenuation of membrane attack formation and indirectly through binding and enhancing activity of complement inhibitors C4B-binding protein and factor H. J Biol Chem. 2011;286:27915–26.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Melin FC, Morgelin M, Vadstrup K, Heinegard D, Aspberg A, Blom AM. The C-type lectin of the aggrecan G3 domain activates complement. PLoS One. 2013;8, e61407.CrossRefGoogle Scholar
  46. 46.
    Sjoberg A, Onnerfjord P, Morgelin M, Heinegard D, Blom AM. The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J Biol Chem. 2005;280:32301–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Happonen KE, Furst CM, Saxne T, Heinegard D, Blom AM. PRELP protein inhibits the formation of the complement membrane attack complex. J Biol Chem. 2012;287:8092–100.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Happonen KE, Saxne T, Aspberg A, Morgelin M, Heinegard D, Blom AM. Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis. Arthritis Rheum. 2010;62:3574–83.CrossRefPubMedGoogle Scholar
  49. 49.
    Acharya C, Yik JH, Kishore A, Van DV, Di Cesare PE, Haudenschild DR. Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: interaction, regulation and role in chondrogenesis. Matrix Biol. 2014;37:102–11.CrossRefPubMedGoogle Scholar
  50. 50.
    Wang Y, Rollins SA, Madri JA, Matis LA. Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc Natl Acad Sci U S A. 1995;92:8955–9.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Okroj M, Heinegard D, Holmdahl R, Blom AM. Rheumatoid arthritis and the complement system. Ann Med. 2007;39:517–30.CrossRefPubMedGoogle Scholar
  52. 52.
    Vergunst CE, Gerlag DM, Dinant H, Schulz L, Vinkenoog M, Smeets TJ, Sanders ME, Reedquist KA, Tak PP. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology (Oxford). 2007;46:1773–8.CrossRefGoogle Scholar
  53. 53.
    Lepus CM, Song JJ, Wang Q, Wagner CA, Lindstrom TM, Chu CR, Sokolove J, Leung LL, Robinson WH. Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis. Arthritis Rheumatol. 2014;66:101–6.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Schmal H, Salzmann GM, Niemeyer P, Langenmair E, Guo R, Schneider C, Habel M, Riedemann N. Early intra-articular complement activation in ankle fractures. Biomed Res Int. 2014;2014:426893.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: therapeutic interventions. J Immunol. 2013;190:3839–47.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Huber-Lang M, Kovtun A, Ignatius A. The role of complement in trauma and fracture healing. Semin Immunol. 2013;25:73–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Recknagel S, Bindl R, Brochhausen C, Gockelmann M, Wehner T, Schoengraf P, Huber-Lang M, Claes L, Ignatius A. Systemic inflammation induced by a thoracic trauma alters the cellular composition of the early fracture callus. J Trauma Acute Care Surg. 2013;74:531–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Ignatius A, Schoengraf P, Kreja L, Liedert A, Recknagel S, Kandert S, Brenner RE, Schneider M, Lambris JD, Huber-Lang M. Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1beta. J Cell Biochem. 2011;112:2594–605.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Hengartner NE, Fiedler J, Schrezenmeier H, Huber-Lang M, Brenner RE. Crucial role of IL1beta and C3a in the in vitro-response of multipotent mesenchymal stromal cells to inflammatory mediators of polytrauma. PLoS One. 2015;10, e0116772.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Martel C, Cointe S, Maurice P, Matar S, Ghitescu M, Theroux P, Bonnefoy A. Requirements for membrane attack complex formation and anaphylatoxins binding to collagen-activated platelets. PLoS One. 2011;6, e18812.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M. Molecular intercommunication between the complement and coagulation systems. J Immunol. 2010;185:5628–36.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Huber-Lang M, Younkin EM, Sarma JV, Riedemann N, McGuire SR, Lu KT, Kunkel R, Younger JG, Zetoune FS, Ward PA. Generation of C5a by phagocytic cells. Am J Pathol. 2002;161:1849–59.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants – a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32:6692–709.CrossRefPubMedGoogle Scholar
  64. 64.
    Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. The role of complement in biomaterial-induced inflammation. Mol Immunol. 2007;44:82–94.CrossRefPubMedGoogle Scholar
  65. 65.
    Noordin S, Shortkroff S, Sledge CB, Spector M. Investigation of the activation of a human serum complement protein, C3, by orthopedic prosthetic particulates. Biomaterials. 2004;25:5347–52.CrossRefPubMedGoogle Scholar
  66. 66.
    DeHeer DH, Engels JA, DeVries AS, Knapp RH, Beebe JD. In situ complement activation by polyethylene wear debris. J Biomed Mater Res. 2001;54:12–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Markus Huber-Lang
    • 1
  • Anita Ignatius
    • 2
  • Rolf E. Brenner
    • 3
  1. 1.Department of Orthopedic Trauma, Hand-, Plastic-, and Reconstructive SurgeryUniversity of UlmUlmGermany
  2. 2.Institute of Orthopedic Research and BiomechanicsUniversity of UlmUlmGermany
  3. 3.Division for Biochemistry of Joint and Connective Tissue Diseases, Department of OrthopedicsUniversity of UlmUlmGermany

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