Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor.
Leukotriene C4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT1R], CysLT2R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT2R. Platelets expressed CysLT1R and CysLT2R proteins. LTC4 induced surface expression of CD62P by wild-type mouse platelets in platelet-rich plasma (PRP) and caused their secretion of thromboxane A2 and CXCL4. LTC4 was fully active on PRP from mice lacking either CysLT1R or GPR99, but completely inactive on PRP from CysLT2R-null (Cysltr2(-/-)) mice. LTC4/CysLT2R signaling required an autocrine ADP-mediated response through P2Y12 receptors. LTC4 potentiated airway inflammation in a platelet- and CysLT2R-dependent manner. Thus, CysLT2R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte-platelet complexes that facilitate inflammation.
Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA 02115;
Hannah E
HE
Cummings
Tao
T
Liu
Chunli
C
Feng
Tanya M
TM
Laidlaw
Pamela B
PB
Conley
Yoshihide
Y
Kanaoka
Joshua A
JA
Boyce
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D017997:Leukotriene C4 / Q000502:physiology* / Q000633:toxicity; D017998:Leukotriene D4 / Q000494:pharmacology; D017999:Leukotriene E4 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics; D015539:Platelet Activation / Q000187:drug effects; D010978:Platelet Factor 4 / Q000378:metabolism; D053657:Platelet-Rich Plasma; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology; D018077:Receptors, Leukotriene / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000502:physiology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000172:deficiency; D013928:Thromboxane A2 / Q000378:metabolism
C486887:OXGR1 protein, mouse; D019007:P-Selectin; D018077:Receptors, Leukotriene; D018048:Receptors, Purinergic P2; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D017997:Leukotriene C4; D010978:Platelet Factor 4; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D017998:Leukotriene D4; D017999:Leukotriene E4; D010047:Ovalbumin; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor