Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling

Abstract

Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybernetic parameters, such as controller, sensor, and effector (VASP phosphorylation, P2Y12, ADORAs and GPIIb/IIIa activity), as well as set points (ADP, adenosine) and interfering control and disturbance variables (ischemia). We demonstrate the impact of the regulated platelet–neutrophil complex (PNC) formation in blood and the resulting damage to the affected inflamed tissue. Taken together, extracellular nucleotide signaling, PNC formation, and tissue damage in IIR can be integrated in a controlled cybernetic circle of platelet function, as introduced through this study.

Semaphorin 7A is protective during inflammatory peritonitis through integrin receptor signaling

“…Recent studies have also suggested that SEMA7A could play a potential part in triggering inflammation in cases of lung injury induced by seawater aspiration ( 12 ) or following lipopolysaccharide challenge ( 13 ) and contribute to metabolic reprogramming in peritoneal macrophages ( 14 ). In a recent study, we were also able to show that PNCs (platelet–neutrophil complexes) are increased in patients with acute myocardial infarction and this is associated with increased levels of SEMA7A ( 15 , 16 ). However, controversial data exist for the role of SEMA7A in the intestinal system, since a study conducted by Kang et al.…”

Systemic immune-inflammation index as a prognostic marker in HER2-positive breast cancer patients undergoing trastuzumab therapy

“…The involvement of platelets in the tumorigenesis of various malignancies has also been demonstrated 22 . Platelets tightly control the actions of neutrophils by forming platelet-neutrophil complexes in the blood and guiding neutrophils into ischemic tissues 23 . Additionally, leaky tumor vasculature allows direct interaction between platelets and tumors.…”

Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury

“…PNCs were identified as CD45 + Ly-6G/C + CD41 + events and expressed as percentage of CD45 + Ly-6G/C + neutrophils. In addition, neutrophil numbers from PBS-treated samples were expressed as percentage of CD45 + leukocytes and compared between animals to rule out variations in blood composition [29].…”

“…Thus, PNCs may contribute to both the thrombotic and inflammatory processes triggered by mIRI [75,89], which is also reflected by increased numbers of circulating PNCs in the blood of patients with acute coronary syndrome [58,65,74]. Furthermore, the number of PNCs in ischemic myocardial tissue correlated with the extent of IIR and mIRI in animal studies [29,50].…”

“…Mechanistically, the formation of platelet neutrophil complexes (PNCs) leads to activation of both cell types triggering the release of cytokines, increased production of ROS, as well as expression of adhesion molecules and cell surface receptors [76]. This activation not only facilitates extravasation of neutrophils and their recruitment to the site of inflammation but also to the site of ischemia, also known as sterile imnflammation or alternatively the ischemic inflammatory response (IIR) [29,75,83]. Thus, PNCs may contribute to both the thrombotic and inflammatory processes triggered by mIRI [75,89], which is also reflected by increased numbers of circulating PNCs in the blood of patients with acute coronary syndrome [58,65,74].…”