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Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease in which a variety of circulating pro-inflammatory cells and dysregulated molecules are involved in disease aetiology and progression. Platelets are an important cellular element in the circulation that can bind several dysregulated molecules (such as collagen, thrombin and fibrinogen) that are present both in the synovium and the circulation of patients with RA. Platelets not only respond to dysregulated molecules in their environment but also transport and express their own inflammatory mediators, and serve as regulators at the boundary between haemostasis and immunity. Activated platelets also produce microparticles, which further convey signalling molecules and receptors to the synovium and circulation, thereby positioning these platelet-derived particles as strategic regulators of inflammation. These diverse functions come together to make platelets facilitators of cellular crosstalk in RA. Thus, the receptor functions, ligand binding potential and dysregulated signalling pathways in platelets are becoming increasingly important for treatment in RA. This Review aims to highlight the role of platelets in RA and the need to closely examine platelets as health indicators when designing effective pharmaceutical targets in this disease.

Key points

  • Platelets have important immune effector functions in rheumatoid arthritis (RA).

  • Platelet signalling pathways are dysregulated in the presence of pro-inflammatory molecules such as collagen, thrombin, fibrinogen and cytokines.

  • Increased (pro-inflammatory) platelet signalling causes platelets to develop antigen-presenting functions and results in dysregulated intercellular aggregation and pathological clot formation.

  • Activated platelets and their thrombo-inflammatory function in RA represent an important risk factor for thrombosis and cardiovascular comorbidities.

  • Activated platelets produce pro-inflammatory microparticles that are present both in the circulation and in the synovium; these microparticles function in systemic inflammatory processes in RA.

  • In an individualized medicine approach, platelet structure and biochemical markers of inflammation would be used during diagnosis and platelet activity monitored during treatment to track immune responses in RA.

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Fig. 1: Platelet involvement in the pathophysiology of rheumatoid arthritis.
Fig. 2: Platelet–immune cell crosstalk in rheumatoid arthritis.
Fig. 3: Platelet receptors involved in inflammatory signalling in rheumatoid arthritis.
Fig. 4: Platelet αIIbβ3 integrin signalling in rheumatoid arthritis.
Fig. 5: Platelet α2β1 integrin signalling in rheumatoid arthritis.
Fig. 6: Platelet GPVI and FcRγ signalling in rheumatoid arthritis.

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Acknowledgements

The work of the authors was funded by the South African Medical Research Council and the National Research Foundation (South Africa; grant number N00345 to E.P.).

Review criteria

A search for original articles published between 1984 and 2018 without language restriction was performed in PubMed, MEDLINE, Google Scholar and Scopus. The search terms used were “platelet rheumatoid arthritis”, “platelet ligands”, “platelet microparticle”, “platelet uptake and secretion”, “platelet receptors”, “platelet signalling pathways” and “immune functions”. All articles identified were reviewed manually for eligibility.

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Nature Reviews Rheumatology thanks J. Semple and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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O.O.-A. researched data for the article. O.O.-A. and E.P. provided substantial contributions to discussion of content. O.O.-A., M.J.P. and E.P. wrote the article and all authors reviewed and/or edited the manuscript before submission.

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Correspondence to Oore-ofe Olumuyiwa-Akeredolu or Etheresia Pretorius.

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Plateletcrit

A measure of the number of platelets present in a blood fraction.

Platelet distribution width

A blood parameter that measures the variability in platelet size distribution.

Mean platelet volume

A measure of the average size of platelets within a blood sample.

Platelet spreading

An indicator of cellular activation that involves reorganization of the actin cytoskeleton to extend filopodia and lamellipodia, thereby converting platelets from biconcave to amorphous cells.

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Olumuyiwa-Akeredolu, Oo., Page, M.J., Soma, P. et al. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol 15, 237–248 (2019). https://doi.org/10.1038/s41584-019-0187-9

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