1. Academic Validation
  2. Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

  • Immunol Res. 2022 Apr;70(2):185-196. doi: 10.1007/s12026-021-09258-5.
Matthias Bock  # 1 2 Christian B Bergmann  # 1 3 4 Sonja Jung 1 Peter Biberthaler 3 Laura Heimann 1 Marc Hanschen 5 6
Affiliations

Affiliations

  • 1 Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.
  • 2 Department of Cardiology, School of Medicine, German Heart Centre Munich, Technical University of Munich, Lazarettstr. 36, 80636, Munich, Germany.
  • 3 Department of Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.
  • 4 Division of Research, Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
  • 5 Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany. Marc.Hanschen@mri.tum.de.
  • 6 Department of Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany. Marc.Hanschen@mri.tum.de.
  • # Contributed equally.
Abstract

CD4+FoxP3+ regulatory T cells (CD4+ Tregs) are known to dampen inflammation following severe trauma. Platelets were shown to augment their posttraumatic activation in burn injury, but the exact mechanisms remain unclear. We hypothesized that platelet activation mechanisms via GPIIb/IIIa, fibrinogen, and PAR4 have an immunological effect and modulate CD4+ Treg activation early after trauma. Therefore, C57Bl/6 N mice were injected with tirofiban (GPIIb/IIIa inhibition), ancrod (fibrinogen splitting Enzyme), or tcY-NH2 (selective PAR4 Antagonist peptide) before inducing a third-degree burn injury of 25% of the total body surface area. Changes in coagulation, and local and systemic CD4+ Treg activity were assessed via rotational thromboelastometry (ROTEM®) and phospho-flow cytometry 1 h post intervention. The inhibition of GPIIb/IIIa and fibrinogen locally led to a higher basic activity of CD4+ Tregs compared to non-inhibited Animals. In contrast, PAR4 disruption on platelets locally led to an increased posttraumatic activation of CD4+ Tregs. Fibrinogen led to complete elimination of coagulation, whereas GPIIb/IIIa or PAR4 inhibition did not. GPIIb/IIIa receptor and fibrinogen inhibition increase CD4+ Tregs activity independently of trauma. Both are crucial for thrombus formation. We suggest platelets trapped in thrombi are unable to interact with CD4+ Tregs but augment their activity when circulating freely. In contrast, PAR4 seems to reduce CD4+ Treg activation following trauma. In summary, GPIIb/IIIa-, PAR4-, and fibrinogen-dependent pathways in platelets modulate CD4+ Treg baseline activity, independently from their hemostatic functionality. PAR4-dependent pathways modulate the posttraumatic interplay of platelets and CD4+ Tregs.

Keywords

CD4+ regulatory T cells; Fibrinogen; Glycoprotein IIb/IIIa; Protease-activated receptor 4; Thrombocytes; Trauma; αIibβ3.

Figures
Products