The NLRP3 inflammasome in platelets – form, functions, and future of the complex

Platelets are anucleate cells that primarily facilitate thrombosis and hemostasis but can also act as mediators of vascular inflammation in disease. Platelets are typically understood to do this through the release of pre-formed chemokines coupled with direct heterotypic interactions with a variety of immune cells. However, an alternative mode of action has been described where platelets are able to undertake de novo synthesis of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The primary mechanism to produce these inflammatory mediators is the activation of the NACHT leucine-rich repeat pyrin domain-containing protein 3 (NLRP3) inflammasome, a multi-protein complex that processes IL-1β and IL-18 through caspase activation. The presence and characteristics of the NLRP3 inflammasome have been widely described in a variety of nucleated cells, although its role in anucleate platelets is less clear. In the last decade, the presence of the inflammasome has been reported in platelets and linked to several diseased states including sickle cell disease, acute coronary syndrome, sepsis, and viral hemorrhagic fever. This emerging new biology of platelets, its role in platelet function, vascular inflammation, and other related areas of exploration are critically reviewed here.

Plain Language Summary

Platelets are blood cells that are critical for effective hemostasis but also drive pathological thrombosis. While these are considered as the classic roles of platelets in the body, they also play a role in immunity, inflammation, and infection. One recent aspect of the inflammatory activity of platelets has been around the presence and activity of a large protein complex called the NLRP3 inflammasome. When the NLRP3 inflammasome is activated by cellular or pathogen danger signals, several smaller proteins come together to form a large functional unit which allows the cell to produce an inflammatory signal that can activate other cells. It is important to understand what the NLRP3 inflammasome in platelets does in health and disease, as it can drive a hyperactive immune environment that can cause negative effects.

In platelets, the role of the NLRP3 inflammasome has only begun to be explored, and there have been many recent studies on this topic; however, they often have found slightly different or conflicting results. In this review, the current literature on the platelet NLRP3 inflammasome is brought together and critiqued, highlighting common themes, but also differences between these studies. There remains a great deal still to be understood about the presence and activity of the NLRP3 inflammasome in platelets, as well as controversies and new areas which need to be explored.