Mast cell-derived histamine is necessary for platelet-activating factor mediated systemic immunosuppression (IRC4P.606)

Abstract

Abstract Platelet-activating Factor (PAF) activates many cell types via the G-protein coupled PAF-receptor (PAF-R). Systemic PAF-R activation exerts acute pro-inflammatory, as well as delayed systemic immunosuppressive effects in vivo. PAF enzymatic synthesis and degradation is tightly regulated, but reactive oxygen species from oxidative stressors, such as UVB, chemotherapy and cigarette smoke, generate PAF-like species via the unregulated oxidation of membrane lipids. The systemic immunosuppressive effects of these pro-oxidative stressors are due to PAF-R signaling. This work establishes the role of the mast cell (MC) and the soluble mediators involved in PAF-R-mediated immunosuppression. Using a contact hypersensitivity model, we show that PAF loses its immunosuppressive effects in MC-deficient (Wsh) mice, a phenotype rescued by dermal reconstitution of Wsh mice with WT bone marrow derived MCs. Use of PAF-R-deficient Wsh mice suggests that the MC PAF-R is necessary and sufficient to mediate PAF-R systemic suppression, in a process attenuated by COX-2 and TGF-β inhibitors. Finally, by transplanting histamine (histidine decarboxylase-null) deficient MCs, we demonstrate that this pathway requires MC-derived histamine release. These studies fit with the hypothesis that MC PAF-R activation with resultant histamine release mediates PAF-R systemic immunosuppression.