Platelets Participate in Synovitis via Cox-1–Dependent Synthesis of Prostacyclin Independently of Microparticle Generation

Abstract

In addition to the well-described role of platelets in thrombosis, a growing body of evidence implicates platelets in diverse inflammatory responses. We recently showed platelets can contribute to the pathophysiology of inflammatory arthritis via IL-1–containing microparticles. In this study, we demonstrate that platelets, and not platelet microparticles, actively contribute to synovitis via production of proinflammatory prostacyclin in an autoimmune arthritis model. Using both genetic and pharmacologic approaches, we establish that paracrine production of prostacyclin proceeds in the absence of cyclooxygenase-2. Furthermore, we also demonstrate that prostacyclin generation can arise via transcellular collaboration between platelets and fibroblast-like synoviocytes. In addition to shedding light on an unappreciated pathway of lipid synthesis in arthritis, we further delineate a novel effector activity by which platelets can contribute to inflammatory disease.

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

“…It was previously shown using the K/BxN serum transfer model of autoimmune arthritis that platelet COX-1 could generate large quantities of extracellular prostaglandin H 2 , which itself was metabolized transcellularly by the prostaclycin synthase expressed by fibroblast-like synoviocytes (53). The generation of prostacyclin by fibroblast-like synoviocytes amplifies inflammation, and, accordingly, the ablation of the gene coding for prostacyclin receptor reduces arthritis in vivo (54).…”

Platelets can enhance vascular permeability

“…[58][59][60] Prostacyclin is present in mouse and human arthritic joints, 62,63 and we have demonstrated that platelets produce prostacyclin with synoviocytes using a transcellular mechanism during arthritis. 19,62,64 The balance between such mediators may thus impact platelet functions and guide the fate of the vasculature: its leakage or its preservation. Finally, arthritis is dependent on platelet GPVI activation and independent of GPIb.…”

“…[58][59][60] Prostacyclin is present in mouse and human arthritic joints, 62,63 and we have demonstrated that platelets produce prostacyclin with synoviocytes using a transcellular mechanism during arthritis. 19,62,64 The balance between such mediators may thus impact platelet functions and guide (A) Serotonin concentrations were measured in whole blood from mast cell-deficient mice (Kit W-sh ), neutrophil-depleted mice, platelet-depleted mice, and their corresponding control mice using an ELISA serotonin kit. (B) Serotonin concentration was measured in platelet isolated from WT and Slc6a4 Ϫ/Ϫ mice.…”

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

“…In particular, a substantial contribution of platelet-derived factors has been suggested in rheumatoid arthritis (RA; reviewed in detail elsewhere [53]) as platelet glycoprotein IIb/IIIa can be detected in the synovium of patients with RA [54,55]. Moreover, the activation marker P-selectin is higher in platelets from patients with active RA than those in remission [56] and elevated levels of PMP and soluble CD40L as well as P-selectin are reported in individuals suffering from RA [57,58,59,60,61,62,63].…”

“…Interestingly, it was shown that GPVI is the relevant receptor for this effect, while neither thromboxane production or blockade of its receptor nor GPIbα was necessary in this context (see Table 3 and Table 4) [70]. Furthermore, it was shown that genetic depletion of COX-1 in mice resulted in an ameliorated disease course in an animal model of RA [53]. Even more surprising, treatment with P2Y 12 receptor antagonists like prasugrel leads to an aggravated disease course [70,73]; however, to support the potential human relevance, several case reports of patients developing spontaneous joint inflammation after clopidogrel intake exist [74,75,76,77,78,79].…”