Cerebral malaria (CM) is a major complication of berghei infection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitizedRBCs to the endothelial cell. In this article, we report that IFN- treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-␣). In addition, IFN--treated P. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN- has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.
Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Platelets have been long described as markers of transplant rejection, but the contribution of platelets to transplant rejection has not been critically examined. We now demonstrate that following T-cell initiation of allograft rejection platelets contribute to T-cell recruitment, increased plasma inflammatory mediators, and accelerate T-cell meditated skin graft rejection. Prior work from our lab has shown that platelets secrete glutamate when activated, which then induces platelet thromboxane production by signaling through platelet expressed ionotropic glutamate receptors. Glutamate receptor antagonists therefore represent novel inhibitors of platelet accelerated inflammation. We have found that plasma glutamate is increased in mice that receive skin grafts and that mice treated with glutamate receptor antagonists have improved graft survival and decreased plasma thromboxane, platelet factor 4 (PF4/CXCL4) and IFNγ. Taken together, our work now demonstrates that subsequent to T-cell initiation of skin graft rejection, platelets contribute to further T-cell recruitment and that by blunting glutamate mediated platelet activation, graft survival is improved.
High density lipoprotein has anti-inflammatory effects in addition to mediating reverse cholesterol transport. While many of the chronic anti-inflammatory effects of high density lipoprotein (HDL) are attributed to changes in cell adhesion molecules, little is known about acute signal transduction events elicited by HDL in endothelial cells. We now show that high density lipoprotein decreases endothelial cell exocytosis, the first step in leukocyte trafficking. ApoA-I, a major apolipoprotein of HDL, mediates inhibition of endothelial cell exocytosis by interacting with endothelial scavenger receptor-BI which triggers an intracellular protective signaling cascade involving protein kinase C (PKC). Other apolipoproteins within the HDL particle have only modest effects upon endothelial exocytosis. Using a human primary culture of endothelial cells and murine apo-AI knockout mice, we show that apo-AI prevents endothelial cell exocytosis which limits leukocyte recruitment. These data suggest that high density lipoprotein may inhibit diseases associated with vascular inflammation in part by blocking endothelial exocytosis.
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