TY - JOUR
T1 - The podoplanin-CLEC-2 axis inhibits inflammation in sepsis
AU - Rayes, Julie
AU - Lax, Sian
AU - Wichaiyo, Surasak
AU - Watson, Stephanie
AU - Di, Ying
AU - Lombard, Stephanie
AU - Grygielska, Beata
AU - Smith, Stuart
AU - Skordilis, Kassiani
AU - Watson, Steve
PY - 2017/12/21
Y1 - 2017/12/21
N2 - Platelets play a critical role in vascular inflammation through the podoplanin and collagen/fibrin receptors, C-type-lectin-like-2 (CLEC-2) and glycoprotein VI (GPVI), respectively. Both receptors regulate endothelial permeability and prevent perivascular bleeding in inflammation. Here, we show that platelet-specific deletion of CLEC-2 but not GPVI leads to enhanced systemic inflammation and accelerated organ injury in two mouse models of sepsis - intra-peritoneal lipopolysaccharide and cecal ligation and puncture. CLEC-2 deficiency is associated with reduced numbers of podoplanin-expressing macrophages despite increased cytokine and chemokine levels in the infected peritoneum. Pharmacological inhibition of the interaction between CLEC-2 and podoplanin regulates immune cell infiltration and the inflammatory reaction during sepsis, suggesting that activation of podoplanin underlies the anti-inflammatory action of platelet CLEC-2. We suggest podoplanin-CLEC-2 as a novel anti-inflammatory axis regulating immune cell recruitment and activation in sepsis.
AB - Platelets play a critical role in vascular inflammation through the podoplanin and collagen/fibrin receptors, C-type-lectin-like-2 (CLEC-2) and glycoprotein VI (GPVI), respectively. Both receptors regulate endothelial permeability and prevent perivascular bleeding in inflammation. Here, we show that platelet-specific deletion of CLEC-2 but not GPVI leads to enhanced systemic inflammation and accelerated organ injury in two mouse models of sepsis - intra-peritoneal lipopolysaccharide and cecal ligation and puncture. CLEC-2 deficiency is associated with reduced numbers of podoplanin-expressing macrophages despite increased cytokine and chemokine levels in the infected peritoneum. Pharmacological inhibition of the interaction between CLEC-2 and podoplanin regulates immune cell infiltration and the inflammatory reaction during sepsis, suggesting that activation of podoplanin underlies the anti-inflammatory action of platelet CLEC-2. We suggest podoplanin-CLEC-2 as a novel anti-inflammatory axis regulating immune cell recruitment and activation in sepsis.
U2 - 10.1038/s41467-017-02402-6
DO - 10.1038/s41467-017-02402-6
M3 - Article
C2 - 29269852
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 2239
ER -