Cleavage fragments of the third complement component (C3) enhance stromal derived factor-1 (SDF-1)-mediated platelet production during reactive postbleeding thrombocytosis.
We hypothesized that the third complement component (C3) cleavage fragments (C3a and (des-Arg)C3a) are involved in stress/inflammation-related thrombocytosis, and investigated their potential role in reactive thrombocytosis induced by bleeding. We found that platelet counts are lower in C3-deficient mice in response to excessive bleeding as compared to normal littermates and that C3a and (des-Arg)C3a enhance stromal-derived factor-1 (SDF-1)-dependent megakaryocyte (Megs) migration, adhesion and platelet shedding. At the molecular level, C3a stimulates in Megs MAPKp42/44 phosphorylation, and enhances incorporation of CXCR4 into membrane lipid rafts increasing the responsiveness of Megs to SDF-1. We found that perturbation of lipid raft formation by statins decreases SDF-1/C3a-dependent platelet production in vitro and in an in vivo model statins ameliorated post-bleeding thrombocytosis. Thus, inhibition of lipid raft formation could find potential clinical application as a means of ameliorating some forms of thrombocytosis.
Wysoczynski
M
M
Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Kucia
M
M
Ratajczak
J
J
Ratajczak
M Z
MZ
D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D015926:Complement C3a / Q000502:physiology*; D006470:Hemorrhage / Q000503:physiopathology*; D006801:Humans; D021962:Membrane Microdomains / Q000502:physiology; D010976:Platelet Count; D019718:Receptors, CXCR4 / Q000502:physiology; D011951:Receptors, Complement / Q000032:analysis; D015398:Signal Transduction; D013922:Thrombocytosis / Q000503:physiopathology*; D034061:Thrombopoiesis
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; D011951:Receptors, Complement; C044541:complement C3a, des-Arg-(77)-; D015926:Complement C3a