Heart attacks or strokes might seem to be sudden events, but they are the consequences of a condition called atherosclerosis, which can be decades in the making. Atherosclerosis involves the accumulation of lipids and immune cells into structures called plaques in the blood-vessel wall. If these plaques become unstable they can rupture, blocking blood flow and so depriving tissues such as the heart and brain of oxygen, respectively triggering a heart attack or a stroke. Identifying precisely how plaques grow at cellular and molecular scales is therefore crucial for understanding and so treating atherosclerosis. Writing in Science Translational Medicine, Barrett et al.1 enrich our thinking about how atherosclerosis evolves, providing evidence that platelets in the blood promote the formation of bigger, more dangerous plaques by shaping the function of immune cells.
Monocytes are a class of short-lived immune cell crucial to host defence. They survey their environment, patrolling the vasculature and frequently migrating in and out of the blood to scout for injuries or infections. This movement is aided by endothelial cells, which demarcate the border between blood and tissue, and which produce a panoply of monocyte-attracting chemical messengers, enabling monocyte surveillance of and migration across the blood-vessel wall. Platelets — blood-cell fragments best known for making blood clots — likewise help monocytes to infiltrate the vessel wall by adhering to the cells to form monocyte–platelet aggregates. Precisely how such aggregates promote migration is not clear, but it is known that platelets can deliver a variety of mediators to which monocytes can respond2.
Because of their role in monitoring the vasculature, monocytes are key to the development of atherosclerosis. Voracious eaters, they ingest lipids that accrue in plaques, before morphing into larger, less agile macrophages. As this transformation occurs, the cells can wreak inflammatory havoc, contributing to a feed-forward loop that generates bigger, rupture-prone plaques3. But because monocytes are crucial for host defence, eliminating them entirely is not therapeutically viable. Identifying and blocking factors involved in monocyte recruitment to plaques might, however, be an alternative strategy.
Barrett and colleagues investigated interactions between platelets, monocytes and their descendent macrophages in mice that have abnormally high levels of cholesterol — a risk factor for atherosclerosis. They observed that platelets adhere to monocytes in blood more readily when mice have high cholesterol levels, bolstering the idea that monocyte–platelet aggregates augment monocyte recruitment to growing plaques. In parallel, the authors performed single-cell RNA sequencing of immune cells retrieved from plaques, and found an increase in platelet-specific factor Pf4 on macrophages, suggesting that platelet adherence persisted beyond monocyte recruitment. Platelets, it seemed, were also aggregating with macrophages.
This liaison spells trouble. The group used specific antibodies to deplete platelets in a genetically engineered strain of mouse susceptible to atherosclerosis, and compared the macrophages of these animals with those of counterparts that had not received platelet-depleting antibodies. Single-cell RNA sequencing revealed that exposure to platelets triggers increased production and release of plaque-enhancing inflammatory molecules by macrophages. Interleukin-1β is one such mediator — and, indeed, therapeutic blockade of this protein in humans attenuates cardiovascular disease4.
Next, Barrett et al. provided further evidence that the presence of platelets accelerates plaque growth. In addition to inducing inflammatory-molecule production, platelets impaired macrophages’ capacity to ingest dying cells through efferocytosis, increasing the number of undigested dying cells in plaques — a phenomenon that increases the likelihood of plaque rupture. Thus, platelets promote atherosclerosis by fostering monocyte recruitment to plaques and by reprogramming macrophage function (Fig. 1).
The authors next investigated the factors that govern the switch in macrophage function. Two transcription factors, suppressor of cytokine signalling 1 (SOCS1) and SOCS3, are known to influence macrophage behaviour5. Specifically, a low ratio of SOCS1 to SOCS3 triggers gene-expression patterns that lead to inflammatory characteristics, whereas a high ratio prompts tissue-repairing traits. The team found that macrophages taken from plaques in platelet-depleted mice had a higher SOCS1:SOCS3 ratio than did macrophages from untreated animals, indicating that platelets somehow alter this pathway in macrophages to trigger inflammatory characteristics.
Finally, Barrett et al. asked whether their findings might be applicable to humans. They found that, in a group of women, the platelet count — and expression of genes that encode SOCS3 and interleukin-1β — was higher in those who had had a heart attack than in those who had not had one. Moreover, the authors report an inverse relationship between the SOCS1:SOCS3 ratio and markers of platelet activation in people with peripheral-artery disease. Thus, this mechanism is potentially relevant to human disease.
Barrett and colleagues’ results are intriguing. Platelet blood-clotting ability serves an essential function in wound healing, but it can be detrimental in the wrong context. Blood-thinning, anti-clot drugs, such as clopidogrel or aspirin, have well-documented therapeutic effects in preventing blood clots. The current study suggests that blocking platelets might have collateral antiatherosclerotic benefits, which aligns with previous work6.
Of course, many questions remain. For instance, it is unclear precisely how platelets foster monocyte recruitment and how they reprogram macrophages. There are clues to be found in other work, given that platelets are a source of various immune mediators2,7. Barrett et al. suggest that platelets stimulate macrophages by releasing the protein S100A9, which triggers the inflammatory TLR signalling pathway in macrophages, but this possibility requires further exploration. Another question is whether distinct types of platelet have evolved for specialized cell communication. In support of this idea, research8 suggests that large platelet-producing cells called megakaryocytes, which reside in different locations, have differing functions. Finally, it will be important to know whether all macrophages are equally affected by platelet instruction, or whether the partnership is specific to certain stages of development, anatomical locations or times.
The authors caution against drawing sweeping conclusions, and, indeed, there are caveats to the study that should be considered. For instance, it would be useful to reduce platelet levels by approaches other than the anti-CD42b antibody used here. This antibody is expected to deplete platelets only transiently, and it might have collateral, unforeseen effects. In addition, it would be valuable to visualize the aggregates in vivo, perhaps using electron microscopy, to obtain a clear picture of what a macrophage–platelet aggregate really looks like. Finally, future work will need to determine whether this phenomenon occurs broadly in other situations involving monocyte recruitment and consequent macrophage activity, for instance in infected or injured tissue.
Nevertheless, the study builds on a long line of work implicating platelets, monocytes and macrophages as key contributors to atherosclerosis. The conceptual power of exploring how immune and blood-clotting pathways intersect, the insights into monocyte and macrophage function, and the corroborating human data, are all worthy of further exploration.
Nature 577, 323-324 (2020)