Editorial.
The requirement for platelets to maintain haemostasis has led to the established long term use of aspirin and P2Y12antagonists for secondary prevention of cardiovascular events arising from arterial thrombi, and the acute clinical use of glycoprotein GPIIb/IIIa (integrin αIIbβ3) inhibitors to prevent reactive restenosis after coronary angioplasty. There is now an increasing appreciation and understanding that platelet activation also occurs during host defence against infection. In this regard, the functional characteristics of platelets are often causal to the ensuring inflammatory response against various bacterial, viral, or fungal pathogens, in a multitude of organs (Semple et al ., 2014; Yeaman 2011). Similar behaviours of platelets are also observed when the inappropriate activation of inflammatory processes lead to the pathogenesis of a plethora of diseases, including asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, eczema, atherosclerosis, cardiovascular ischaemia-reperfusion injury; and neurological disorders for example multiple sclerosis, Parkinsons disease, and Alzheimer’s disease. A simple bibliographical search, using the terms ‘platelets’ and ‘inflammation’ on PubMed® returns 23,966 articles (conducted October 2023). Interest in these pro-inflammatory functions of platelets has been expanding at an increasing rate each decade from the 1980s to the present day (2022 alone returned 2,031 articles for ‘platelets’ and ‘inflammation’).
Some of these diseases have altered haemostasis with inflammation, and the rationale for analysing the efficacy of existing anti-platelet drugs in these contexts is self-evident. However, our understanding of platelet activity is now evolving to question how we might control the non-thrombotic functions of platelets specifically induced during inflammatory diseases and infections where no alterations in haemostasis exist, as promulgated by the concept of there being an existence of a dichotomy (or polytomy) in platelet function (Page et al., 1988). Will existing anti-platelet drugs confer sufficient anti-inflammatory effects, or are novel approaches needed to control pro- inflammatory platelet functions? The answer to this question might lead to a different class of anti-platelet agents that suppress inflammation whilst preserving haemostasis and avoiding the unwanted risk of haemorrhage.
Nucleotides and nucleosides are essential in the control of both haemostasis and inflammation (Burnstock 2014; Ferrari et al ., 2016; Gachet 2006; Idzko et al ., 2014). The study of the extracellular ‘purinome’, and the receptors involved during inflammation is therefore one starting point in understanding how platelets might get activated in this context (Jacobson et al., 2011). It is therefore the topic for this themed review series in the British Journal of Pharmacology: ‘Platelet purinergic receptors and non-thrombotic diseases’. The understanding of platelet activation via the P2Y12 receptor in the context of inflammation is discussed in cardiovascular and non-cardiovascular conditions, recognising that direct and pleotropic effects of thienopyridines and ticagrelor can make the pharmacological interpretation of clinical studies complex (Parker & Storey 2023). This is complemented by a review of evidence for P2Y12 activation in the dysregulated immune response during sepsis and the challenges associated with interpreting a dynamically changing inflammatory and then conversely immunosuppressed state, combined with activation of haemostatic pathways by Amoafo and colleagues (Amoafo et al ., 2023). In another review, the potential role for adenosine is discussed (Boncler et al., 2023). Adenosine activation of platelet A2A and A2B receptors suppresses platelet activation during haemostasis. The potential control of platelet activation in the context of adenosine suppression of inflammation in thus introduced, including approaches to creating more stable analogues of adenosine (Boncler et al ., 2023). Lastly, the discovery that P2Y1 receptor activation by various endogenous extracellular nucleotides can lead to selective platelet inflammatory functions and not aggregation (Arkless et al ., 2023), leads to a discussion about the selective control of platelet activation by P2Y1 during inflammation compared to haemostasis, and the potential for safe anti-platelet drugs that suppress inflammation whilst preserving haemostasis (Pan et al ., 2023).
Notwithstanding the possibility for other purinergic receptors expressed by platelets to also have roles in inflammation (the ligand gated ion channel P2X1 -activated by ATP; and the GPCR P2Y14 -activated by UDP-glucose), it is hoped that this themed issue in the British Journal of Pharmacology opens further debate in the exploration of platelet function during inflammation, as controlled by the ‘purinome’.