Platelet and endothelial cell P-selectin are required for host defense against Klebsiella pneumoniae-induced pneumosepsis

Abstract

To cite this article: de Stoppelaar SF, van't Veer C, Roelofs JJTH, Claushuis TAM, de Boer OJ, Tanck MWT, Hoogendijk AJ, van der Poll T.Platelet and endothelial cell P-selectin are required for host defense against Klebsiella pneumoniae-induced pneumosepsis. J Thromb Haemost 2015; 13: 1128-38.Summary. Background: Sepsis is associated with activation of platelets and endothelial cells accompanied by enhanced P-selectin surface expression. Both platelet-and endothelial P-selectin have been associated with leukocyte recruitment and induction of inflammatory alterations. Klebsiella (K.) pneumoniae is a common human sepsis pathogen, particularly in the context of pneumonia. Methods: Wild-type (WT) and P-selectin-deficient (Selp À/ À ) mice or bone marrow chimeric mice were infected with K. pneumoniae via the airways to induce pneumosepsis. Mice were sacrificed during early (12 h after infection) or late-stage (44 h) sepsis for analyses, or followed in a survival study. Results: Selp À/À mice displayed 10-1000-fold higher bacterial burdens in the lungs, blood and distant organs during late-stage sepsis. P-selectin deficiency did not influence leukocyte recruitment to the lungs, but was associated with decreased platelet-monocyte complexes and increased cytokine release. Bone marrow transfer studies revealed a role for both platelet and endothelial cell P-selectin as mice deficient in platelet or endothelial cell P-selectin displayed an intermediate phenotype in bacterial loads and survival compared with full wild-type or full knockout control mice. Conclusion: Both platelet and endothelial cell P-selectin contribute to host defense during Klebsiella pneumosepsis.

Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis

“…This model is associated with a gradually growing bacterial load in the lungs with subsequent dissemination to distant body sites and organ injury, allowing studies on the role of components of innate immunity in early host defense as well as tissue damage during late-stage infection. We demonstrated that the number of platelets is a major denominator of their role in pneumosepsis [19], and identified platelet P-selectin [11] and GPVI [12] as mediators contributing to the control of bacterial growth. The current study suggests that platelet δ granules may contribute to thrombocytopenia in severe infection and can most likely thereby impair antibacterial defense during pneumonia-derived sepsis.…”

“…We previously used this model of pneumonia-derived sepsis caused by the common human pathogen K. pneumoniae to study the role of platelets and platelet receptors in the host response to severe infection [11, 12, 19, 37]. This model is associated with a gradually growing bacterial load in the lungs with subsequent dissemination to distant body sites and organ injury, allowing studies on the role of components of innate immunity in early host defense as well as tissue damage during late-stage infection.…”

“…Recent investigations have shown that platelets aid in host defense in multiple ways, including P-selectin [11], glycoprotein (GP)VI [12], and GPIb [13, 14]. Platelets can crucially modulate immunity during infection and inflammation, influencing, for example, leukocyte recruitment, cytokine production, and neutrophil extracellular trap formation [15-18].…”

Measuring and interpreting platelet-leukocyte aggregates

“…In this context, thrombocytopenia increases bacterial burden in some inflammatory settings, such as Streptococcus pneumoniae -induced pneumonia while not affecting neutrophil infiltration (129). Furthermore, P-selectin-deficiency results in reduced circulating PMAs during Klebsiella pneumoniae -induced pneumonia, but has no effect on pulmonary leukocyte sequestration (130). However, thrombin inhibition reduces PNA formation in vitro and exacerbates sepsis in K. pnemoniae -induced pneumosepsis, but fails to reduce neutrophil recruitment or NET formation in vivo (131).…”

Purinergic Receptors in Thrombosis and Inflammation

“…45,46 Specifically, the involvement of platelet P2Y 12 in sepsis has been suggested on the grounds of the inhibitory effect of the P2Y 12 antagonist ticagrelor on platelet-neutrophil aggregate formation, neutrophil recruitment, and lung damage in mice subjected to cecal ligation and puncture. 47 However, because ticagrelor also inhibits adenosine uptake, the possibility that its protective effect might be related at least partially to its effect on adenosine metabolism cannot be ruled out.…”