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Platelet glycoprotein VI aids in local immunity during gram-negative pneumonia derived sepsis

Theodora A.M. Claushuis, Alex F. de Vos, Bernhard Nieswandt, Louis Boon, Joris J.T.H. Roelofs, Onno J. de Boer, Cornelis J. van 't Veer and Tom van der Poll

Key points

  • Platelet glycoprotein (GP)VI aids in local immunity in gram-negative pneumonia derived sepsis.

  • GPVI, CLEC2 and neutrophils do not play a major role in vascular integrity during pneumosepsis.

Abstract

Platelet collagen receptor glycoprotein(GP)VI and podoplanin receptor C-type lectin-like receptor (CLEC-)2 are receptors implicated in platelet activation that both signal via an immunoreceptor-tyrosine-based activation motif. Platelets are necessary for host defense and prevention of hemorrhage during sepsis, but the role of platelet GPVI and CLEC2 herein is unknown. To investigate this we infected mice depleted of platelet GPVI or CLEC2 by antibody treatment or GPVI-/- mice with the common human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia derived sepsis. GPVI ligand collagen and CLEC2 ligand podoplanin were constitutively present in the lung, whereas GPVI ligands fibrin and histones were induced during pneumonia. Mice depleted of GPVI and GPVI-/- mice showed increased bacterial growth in lung and GPVI-/- mice also in distant body sites, during late stage infection. In spite of higher bacterial loads, GPVI depleted mice showed reduced platelet numbers, platelet activation and platelet-leukocyte complex formation in the bronchoalveolar space. Consistently, in human whole blood, GPVI stimulation of platelets increased platelet-leukocyte complex formation and leukocyte activation, which was accompanied by enhanced phagocytosis of Klebsiella. GPVI depleted mice showed increased lung hemorrhage during infection, but not to the extent as observed in platelet depleted mice and in GPVI-/- mice lung bleeding was not significantly different from that in wild-type mice. CLEC2 depletion did not affect any of the responses during pneumonia. These results suggest that platelet GPVI, but not CLEC2, contributes to local host defense during pneumonia derived sepsis by enhancing leukocyte functions.

  • Submitted June 14, 2017.
  • Accepted November 25, 2017.