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

  • Dong Hyun Sohn1, 2Email author,

    Affiliated with

    • Jeremy Sokolove1, 2Email author,

      Affiliated with

      • Orr Sharpe1, 2Email author,

        Affiliated with

        • Jennifer C Erhart3, 4,

          Affiliated with

          • Piyanka E Chandra1, 2,

            Affiliated with

            • Lauren J Lahey1, 2,

              Affiliated with

              • Tamsin M Lindstrom1, 2,

                Affiliated with

                • Inyong Hwang1, 2,

                  Affiliated with

                  • Katherine A Boyer3, 4,

                    Affiliated with

                    • Thomas P Andriacchi3, 4 and

                      Affiliated with

                      • William H Robinson1, 2Email author

                        Affiliated with

                        Arthritis Research & Therapy201214:406

                        DOI: 10.1186/ar3892

                        Published: 12 September 2012

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


                        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.PubMedView Article
                        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
                        3. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440:237–241.PubMedView Article
                        4. Smiley ST, King JA, Hancock WW: Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J Immunol 2001, 167:2887–2894.PubMed
                        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.PubMedView Article


                        © BioMed Central Ltd 2012