Inositoylated Platelet-Activating Factor (Ino-C2-PAF) Modulates Dynamic Lymphocyte–Endothelial Cell Interactions and Alleviates Psoriasis-Like Skin Inflammation in Two Complementary Mouse Models

Abstract

Psoriasis, a tumor necrosis factor alpha (TNFα)-governed inflammatory disorder with prominent dysregulation of cutaneous vascular functions, has evolved into a model disorder for studying anti-inflammatory therapies. We present experimental in vitro and in vivo data on 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-sn-glycero-3-(R/S)-phosphatidyl-choline (Ino-C2-PAF), the lead compound of a class of synthetic glycosylated phospholipids, in anti-inflammatory therapy. Ino-C2-PAF strongly induced apoptosis only in TNFα-stimulated, but not in untreated human vascular endothelial cells. Moreover, TNFα-induced endothelial adhesion molecules that mediated the rolling and firm adhesion of leukocytes (vascular cell adhesion protein-1 (VCAM-1), E-selectin, and ICAM-1) were selectively downregulated by Ino-C2-PAF. Similarly, expression of L-selectin, VCAM-1 receptor α4β1 integrin , and lymphocyte function-associated antigen-1 on human peripheral blood mononuclear cells was reduced without induction of apoptosis. Functionally, these changes were accompanied by significant impairment of rolling and adhesion of human peripheral blood lymphocytes on TNFα-activated endothelial cells in a dynamic flow chamber system. When the therapeutic potential of Ino-C2-PAF was assessed in two complementary mouse models of psoriasis, K5.hTGFβ1 transgenic and JunB/c-Jun-deficient mice, Ino-C2-PAF led to significant alleviation of the clinical symptoms and normalized the pathological cutaneous changes including vascularization. There were no overt adverse effects. These findings suggested that Ino-C2-PAF is a potential candidate in the therapy of inflammatory skin diseases that include abnormal vascular functions.

Surface Tension and Adsorption Studies by Drop Profile Analysis Tensiometry

“…Figure 3 illustrates the results obtained in [76] for aqueous solutions of Inositol-C2-PAF. These phospholipids, extensively studied in [77][78][79][80][81][82], are the main compounds of eukaryotic plasma membranes which undergo rapid and continuous turnover. The resulting lipid metabolites regulate essential signal pathways.…”

Synthesis of ether lipids: natural compounds and analogues

“…Recent results from our group [41,42] and others renew the interest to develop new ether lipids with promising perspectives to address the modulation of membrane proteins that represent a pertinent strategy for some diseases like cancers. Beside the use of synthetic ether lipids for the prevention or the treatment of cancers via different mechanisms, it must be noted that some synthetic ether lipids (e.g., Ino-C2-PAF) have also the ability to regulate genes involved in innate and acquired immune response [43][44][45] and genes related to inflammation with possible application for the treatment of inflammatory skin diseases [46].…”

Exploring the Pathogenesis of Psoriasis Complicated With Atherosclerosis via Microarray Data Analysis

“…Psoriasis and atherosclerosis have overlapping mechanisms in pathogenic pathways. In psoriasis, myeloid dendritic cells secrete IL12 and IL23, prompting T cells to differentiate into Th1 and Th17 cell subtypes; Th1 cells secrete TNF-α and IFN-γ, which promote the activation and proliferation of keratinocytes and the expression of adhesion molecules such as intercellular adhesion molecule 1 ( 4 ); Th17 cells secrete IL17 and IL22 to promote the proliferation of keratinocytes and angiogenesis in the lesion ( 5 ). In atherosclerosis, the activation of endothelial cells in the plaques of neonatal arteries promotes monocyte and lymphocyte overflow, and granulocyte-macrophage colony stimulating factor can promote the synthesis of IL12 and IL23 by macrophages and dendritic cells, reducing BCL2 and activating Th1 and Th17 responses ( 6 ).…”