Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Activated platelets upregulate β2 integrin Mac-1 (CD11b/CD18) on dendritic cells, which mediates heterotypic cell-cell interaction
H. Nording1, M. Sauter2, R. Steubing3, Y. Sun2, Y. Wang4, B. Zieger5, B. Nieswandt6, C. Kleinschnitz3, D. I. Simon7, H. Langer1
1Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck; 2Kardioimmunologie, Universitätsklinikum Schleswig-Holstein, Lübeck; 3Klinik für Neurologie, Universitätsklinikum Essen, Essen; 4Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, Ohio, US; 5Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine,, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg; 6DFG-Forschungszentrum für Experimentelle Biomedizin, Lehrstuhl I, Rudolf-Virchow-Zentrum, Universität Würzburg, Würzburg; 7Mailbox 569, Cleveland Clinic Foundation, Cleveland, US;

Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell-crosstalk are largely unknown.  We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counter-receptor for platelet GPIbα.

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. Furthermore, GPIbα  blockade reduced leukocyte recruitment in the mCAO stroke model. Inhibition of CD11b or GPIbα but not many other common adhesion receptors both on platelets and DCs led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients. 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 but not preincubation with a blocking antiCD11b antibody 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 the Akt-PI3K-mTOR pathway. Indeed, P-selectin and PSGL1 interaction induced upregulation and activation of CD11b thus allowing for GP1bα CD11b binding to occur. Importantly, specific pharmacological targeting of the GPIbα-Mac-1 interaction site blocked DC-platelet interaction in vitro and in vivo. Thus, platelet-mediated DC recruitment into inflamed tissue may be modulated pharmacologically targeting this interaction.

These results demonstrate that crosstalk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a PSGL1 dependent manner.  


https://dgk.org/kongress_programme/jt2022/aP1947.html