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  3. Activated Platelets Upregulate β2 Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell-Cell Interaction

Activated Platelets Upregulate β2 Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell-Cell Interaction

  • J Immunol. 2022 Apr 1;208(7):1729-1741. doi: 10.4049/jimmunol.2100557.
Henry Nording 1 2 3,  Manuela Sauter 1 3,  Chaolan Lin 1,  Rebecca Steubing 4,  Sven Geisler 5,  Ying Sun 1,  Joel Niethammer 6,  Fréderic Emschermann 7,  Yunmei Wang 8,  Barbara Zieger 9,  Bernhard Nieswandt 10,  Christoph Kleinschnitz 4,  Daniel I Simon 8 11,  Harald F Langer 12 2 3
Affiliations

Affiliations

  • 1 Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.
  • 2 German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany.
  • 3 University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.
  • 4 Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany.
  • 5 Cell Analysis Core Facility, University of Lübeck, Lübeck, Germany.
  • 6 Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Germany.
  • 7 Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tübingen, Germany.
  • 8 Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH.
  • 9 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • 10 Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and.
  • 11 University Hospitals Cleveland Medical Center, Cleveland, OH.
  • 12 Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany; harald.langer@uksh.de.
PMID: 35277420 DOI: 10.4049/jimmunol.2100557
Abstract

Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of Integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding. Inhibition of CD11b or GPIbα led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients and transgenic mouse lines on C57BL/6 background (GPIbα-/-, IL4R-GPIbα-tg, and muMac1 mice). In vivo, inhibition or genetic deletion of CD11b and GPIbα induced a significant reduction of platelet-mediated DC adhesion to the injured arterial wall. Interestingly, only intravascular antiCD11b inhibited DC recruitment, suggesting a dynamic DC-platelet interaction. Indeed, we could show that activated platelets induced CD11b upregulation on Mg2+-preactivated DCs, which was related to protein kinase B (Akt) and dependent on P-selectin and P-selectin glycoprotein ligand 1. Importantly, specific pharmacological targeting of the GPIbα-Mac-1 interaction site blocked DC-platelet interaction in vitro and in vivo. These results demonstrate that cross-talk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a P-selectin glycoprotein ligand 1-dependent manner.

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