POS0445 DISSECTING THE ROLE OF PLATELET FUNCTION IN INFLAMMATORY ARTHRITIS
| Autor: | D. Kimpel, K. Kannan |
|---|---|
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Annals of the Rheumatic Diseases. 81:477.2-477 |
| ISSN: | 1468-2060 0003-4967 |
| DOI: | 10.1136/annrheumdis-2022-eular.4673 |
| Popis: | BackgroundInflammatory autoimmune diseases such as rheumatoid arthritis (RA) show an increase in atherosclerotic cardiovascular disease, and are commonly associated with an increase in platelet counts. Thus, platelets fill a central role in the tenet: Inflammation begets coagulation, and coagulation begets inflammation. We have previously reported that induction of arthritis by the Streptococcal cell wall component peptidoglycan-polysaccharide (PGPS) results in increased platelet numbers, aggregation, activation, and increased expression of P-selectin (CD62-P) and of the costimulatory molecule CD40. These platelets are also more sensitive to stimuli such as ADP and thrombin, which induce dense granule release of serotonin and aggregation. We have also described increased P-selectin expression limited to the joints in mice with acute arthritis. Platelets, generally considered elements of the hemostatic system, are underappreciated for their pro-inflammatory potential.ObjectivesTo further understand the role of platelets in inflammatory arthritis, and distinguish their biochemical and adhesive features we set out to characterize the impact of modulating platelet activity in acute and chronic rodent models of arthritis.MethodsChronic inflammatory arthritis was induced in Lewis rats by a single i.p. injection of PGPS which results in an early phase non-T cell dependent arthritis, and a chronic T cell dependent phase after day 10. An acute inflammatory arthritis was induced in Balb/c mice by the same method. Joint scoring and volume measurement were carried out daily to determine an arthritis severity score.The role of platelets on PGPS arthritis was assessed using a) depletion of platelets using periodic intraperitoneal (IP) anti-platelet antibody, b) blockade of the integrin GPIIb/IIIa with the monoclonal antibody (mAb) abciximab to inhibit activation and aggregation via vWF and fibrinogen. In the acute murine arthritis c) P-selectin deficient mice were assessed for severity of arthritis, and d) wild-type mice were pre-treated with a single IP injection of anti-CD41 (GPIIb) antibody.ResultsDepletion of platelets in rats during the PGPS treatment resulted in amelioration of both the early and chronic phases of disease. We previously demonstrated that TNF is elevated in this model following PGPS injection, so for comparison animals were treated with infliximab, a monoclonal antibody to TNF, with equivalent suppression of both acute and chronic phases of disease. Abciximab, targeting the dual function adhesion and signaling molecule GPIIb/IIIa, did not decrease arthritis, and in fact increased the severity of the chronic phase of arthritis. In the acute murine model, despite the previously described expression of CD62-P in joints and on platelets, the CD62-P knockout mice had no significant difference in arthritis severity. Conversely treatment of wild-type mice with the anti-CD41 to block GPIIb resulted in suppression of the arthritis.ConclusionPlatelet depletion had a dramatic impact on both acute and chronic phases of inflammatory arthritis, which is not unexpected given that platelets carry an array of pro-inflammatory and procoagulant mediators including IL-1, chemokines, vWF, and fibrinogen, as well as an array of adhesion molecules for binding to endothelium, leukocytes, and to other platelets.The increase in chronic arthritis severity despite inhibiting platelet aggregation by blockade of GPIIb/IIIa was unexpected, but may have been due to increased platelet-endothelial binding or platelet-leukocyte aggregation thus exacerbating the chronic T cell phase. Lack of CD62-P appeared to have no influence on acute phase arthritis development. Interestingly anti-CD41, which blocks one part of the GPIIb/IIIa integrin, was effective at ameliorating arthritis in the murine model.Platelets play an often underappreciated role in inflammatory processes, but understanding the mechanisms will require further dissection of the complex nature of these cellular elements which have dual inflammatory and hemostatic roles.Disclosure of InterestsDon Kimpel Speakers bureau: GSK, Consultant of: Aurinia, Krishna Kannan: None declared. |
| Databáze: | OpenAIRE |
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