Platelet–Monocyte Aggregates: Understanding Mechanisms and Functions in Sepsis

Abstract

Platelets have been shown to play an important immunomodulatory role in the pathogenesis of various diseases through their interactions with other immune and nonimmune cells. Sepsis is a major cause of death in the United States, and many of the mechanisms driving sepsis pathology are still unresolved. Monocytes have recently received increasing attention in sepsis pathogenesis, and multiple studies have associated increased levels of platelet–monocyte aggregates observed early in sepsis with clinical outcomes in sepsis patients. These findings suggest platelet–monocyte aggregates may be an important prognostic indicator. However, the mechanisms leading to platelet interaction and aggregation with monocytes, and the effects of aggregation during sepsis are still poorly defined. There are few studies that have really investigated functions of platelets and monocytes together, despite a large body of research showing separate functions of platelets and monocytes in inflammation and immune responses during sepsis. The goal of this review is to provide insights into what we do know about mechanisms and biological meanings of platelet–monocyte interactions, as well as some of the technical challenges and limitations involved in studying this important potential mechanism in sepsis pathogenesis. Improving our understanding of platelet and monocyte biology in sepsis may result in identification of novel targets that can be used to positively affect outcomes in sepsis.

Platelets in pediatric and neonatal sepsis: novel mediators of the inflammatory cascade

“…94 This phenotype has predominated in the sepsis literature to date, with increased platelet monocyte aggregates associated with in Gram positive as opposed to Gram-negative bacteraemia, and a similar increase in aggregates is linked to a higher mortality in adult sepsis. 94 No studies have attempted to replicate these findings in children or neonates, despite known difference in the monocytic response to sepsis in children and neonates. [96][97][98] The P-Selectin-PSGL-1 interaction acts as a key checkpoint in the maturation of monocytes into DCs.…”

“…These are then strengthened with multiple enforcing reactions through HMGB-1-RAGE, CLEC 2-Podoplanin and glycoprotein Ib (GPIb)-CD11b interactions. 94 The resulting complex function is situation-dependent, and is most commonly described with a pro-inflammatory profile, but with substantial evidence of immune regulatory/anti-inflammatory profiles in certain situations. 94 , 95 When pro-inflammatory, it leads to an increase in pro-inflammatory cytokines and chemokines, tumour necrosis factor α (TNF-α), IL-1β, monocyte chemoattractant protein 1 (MCP-1/CCL2) and IL-8 among others.…”

“… 94 The resulting complex function is situation-dependent, and is most commonly described with a pro-inflammatory profile, but with substantial evidence of immune regulatory/anti-inflammatory profiles in certain situations. 94 , 95 When pro-inflammatory, it leads to an increase in pro-inflammatory cytokines and chemokines, tumour necrosis factor α (TNF-α), IL-1β, monocyte chemoattractant protein 1 (MCP-1/CCL2) and IL-8 among others. 94 This phenotype has predominated in the sepsis literature to date, with increased platelet monocyte aggregates associated with in Gram positive as opposed to Gram-negative bacteraemia, and a similar increase in aggregates is linked to a higher mortality in adult sepsis.…”

What Function Do Platelets Play in Inflammation and Bacterial and Viral Infections?

“…-the formation of aggregates with leukocytes and their activation, platelet apoptosis and activation of the vascular endothelium -the activity of the NET network and EET network -the process of absorption and cytotoxicity of PMN and MN cells and the process of cytotoxicity of T cells (references in the text). The pathway of indirect neutralisation of viruses by platelets, via the formation of platelet/neutrophil and platelet/ monocyte aggregates, leads to an increased recruitment of blood immune cells and their activation for the secretion of virucidal substances, which was observed in the case of the infections with flavi-, filo-, bunya-, and arenaviruses, as well as influenza virus, HIV, cytomegalovirus, SARS-CoV-2 and viral sepsis (1,10,11,39,42,44,60,65,76,78,83,85,96,97,115,141). In the case of adenovirus and HIV infections, aggregates of platelets with leukocytes, affecting B cells, increase the synthesis of serum IgG neutralising these viruses (1,23,62).…”

The Platelet Concentrates Therapy: From the Biased Past to the Anticipated Future

“…Therefore, if unfamiliar with this topic, readers are expected to refer to these publications. Despite their limited relevance to PC therapy, several main and supporting functions of platelets, such as aggregation [100][101][102][103], adhesion [103][104][105], activation [102,106,107], growth-factor delivery and roles [108,109], anti-bacteria [110,111], pain-relief [112,113], coagulation [106,107,[114][115][116], and interaction with leukocytes [117,118], should be investigated in more detail in order to understand how living platelets act during preparation and therapeutic processes. Significant advances in understanding platelet biology will enable us to optimize PC preparation further and improve the predictability and quality of PC therapy.…”