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Response to 'Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4' - authors' reply

  • Dong Hyun Sohn1, 2,
  • Jeremy Sokolove1, 2,
  • Orr Sharpe1, 2,
  • Jennifer C Erhart3, 4,
  • Piyanka E Chandra1, 2,
  • Lauren J Lahey1, 2,
  • Tamsin M Lindstrom1, 2,
  • Inyong Hwang1, 2,
  • Katherine A Boyer3, 4,
  • Thomas P Andriacchi3, 4 and
  • William H Robinson1, 2Email author
Contributed equally
Arthritis Research & Therapy201214:406

Published: 12 September 2012


Public HealthCalciumFuture StudyCritical RoleFibrinogen

We thank Oliviero and colleagues for their interest in our recent publication [1] and for reporting their very interesting related experiments [2]. Their results strongly support the concept that extravascular plasma proteins may act as damage-associated molecular patterns, and specifically as Toll-like receptor 4 agonists. In addition, we note that the NALP-3 inflammasome exhibits dependence on Toll-like receptor 4 or other mechanisms of priming of IL-1β transcription, thereby generating pro-IL-1β that can be converted to IL-1β by the activated inflammasome [3].

Although biochemical measurement of plasma and serum were not performed, we suspect the enhanced effect of serum compared with plasma could be related to mediators generated in the clotting process or released by platelets during the clotting process (but not released in the generation of plasma) and not related to the removal of fibrinogen. The observation that fibrinogen is itself able to prime the response to calcium crystal-induced inflammation further supports the role of fibrinogen as a Toll-like receptor 4 agonist [4, 5], as demonstrated by its ability to prime the inflammasome for response to activation by calcium crystals.

We thank Oliviero and colleagues for sharing their results and look forward to future studies elucidating the potentially critical role of plasma proteins as extra-vascular damage-associated molecular patterns.






Authors’ Affiliations

GRECC, VA Palo Alto Health Care System, USA
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, USA
Bone and Joint Center, VA Palo Alto Health Care System, Palo Alto, USA
Department of Mechanical Engineering, Stanford University, Stanford, USA


  1. Sohn DH, Sokolove J, Sharpe O, Erhart JC, Chandra PE, Lahey LJ, Lindstrom TM, Hwang I, Boyer KA, Andriacchi TP, Robinson WH: Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res Ther. 2012, 14: R7-10.1186/ar3555.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Oliviero F, Scanu A, Dayer J-M, Fiocco U, Sfriso P, Punzi L: Response to 'Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4'. Arthritis Res Ther. 2012, 14: 405-PubMed CentralView ArticlePubMedGoogle Scholar
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  5. Sokolove J, Zhao X, Chandra PE, Robinson WH: Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 2011, 63: 53-62.PubMed CentralView ArticlePubMedGoogle Scholar


© BioMed Central Ltd 2012