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

Abstract

We thank Oliviero and colleagues for their interest in our recent publication [1] and for reporting their very interesting related experiments [2]. Th eir results strongly support the concept that extravascular plasma proteins may act as damage-associated molecular patterns, and specifi cally as Toll-like receptor 4 agonists. In addition, we note that the NALP-3 infl ammasome 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 infl ammasome [3]. Although biochemical measurement of plasma and serum were not performed, we suspect the enhanced eff ect 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 fi brinogen. Th e observation that fi brinogen is itself able to prime the response to calcium crystalinduced infl ammation further supports the role of fi brino gen as a Toll-like receptor 4 agonist [4,5], as demon strated by its ability to prime the infl ammasome 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 extravascular damage-associated molecular patterns.