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Volume 11
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10.3390/cells11193009
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Article

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

by
Tiago F. Granja
1,2,†,
David Köhler
2,†,
Veronika Leiss
3,†,
Claudia Eggstein
2,
Bernd Nürnberg
3,
Peter Rosenberger
2 and
Sandra Beer-Hammer
3,*
1
Lusófona’s Research Center for Biosciences & Health Technologies, CBIOS–Universidade, Campo Grande 376, 1749-024 Lisboa, Portugal
2
Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
3
Department of Pharmacology and Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2022, 11(19), 3009; https://doi.org/10.3390/cells11193009
Submission received: 19 April 2022 / Revised: 12 September 2022 / Accepted: 20 September 2022 / Published: 27 September 2022
(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)
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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.
Keywords: platelets; ischemia; ischemic preconditioning; ATP; ADP; adenosine; VASP phosphory-lation; ADORAs; P2Y12 platelets; ischemia; ischemic preconditioning; ATP; ADP; adenosine; VASP phosphory-lation; ADORAs; P2Y12

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MDPI and ACS Style

Granja, T.F.; Köhler, D.; Leiss, V.; Eggstein, C.; Nürnberg, B.; Rosenberger, P.; Beer-Hammer, S. Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling. Cells 2022, 11, 3009. https://doi.org/10.3390/cells11193009

AMA Style

Granja TF, Köhler D, Leiss V, Eggstein C, Nürnberg B, Rosenberger P, Beer-Hammer S. Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling. Cells. 2022; 11(19):3009. https://doi.org/10.3390/cells11193009

Chicago/Turabian Style

Granja, Tiago F., David Köhler, Veronika Leiss, Claudia Eggstein, Bernd Nürnberg, Peter Rosenberger, and Sandra Beer-Hammer. 2022. "Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling" Cells 11, no. 19: 3009. https://doi.org/10.3390/cells11193009

APA Style

Granja, T. F., Köhler, D., Leiss, V., Eggstein, C., Nürnberg, B., Rosenberger, P., & Beer-Hammer, S. (2022). Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling. Cells, 11(19), 3009. https://doi.org/10.3390/cells11193009

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