Modulation of inflammatory platelet-activating factor (PAF) receptor by the acyl analogue of PAF

Abstract

Platelet-activating factor (PAF) is a potent inflammatory mediator that exerts its actions via the single PAF receptor (PAF-R). Cells that biosynthesize alkyl-PAF also make abundant amounts of the less potent PAF analogue acyl-PAF, which competes for PAF-R. Both PAF species are degraded by the plasma form of PAF acetylhydrolase (PAF-AH). We examined whether cogenerated acyl-PAF protects alkyl-PAF from systemic degradation by acting as a sacrificial substrate to enhance inflammatory stimulation or as an inhibitor to dampen PAF-R signaling. In ex vivo experiments both PAF species are prothrombotic in isolation, but acyl-PAF reduced the alkyl-PAF-induced stimulation of human platelets that express canonical PAF-R. In Swiss albino mice, alkyl-PAF causes sudden death, but this effect can also be suppressed by simultaneously administering boluses of acyl-PAF. When PAF-AH levels were incrementally elevated, the protective effect of acyl-PAF on alkyl-PAF-induced death was serially decreased. We conclude that, although acyl-PAF in isolation is mildly proinflammatory, in a pathophysiological setting abundant acyl-PAF suppresses the action of alkyl-PAF. These studies provide evidence for a previously unrecognized role for acyl-PAF as an inflammatory set-point modulator that regulates both PAF-R signaling and hydrolysis.

New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

“…First, there is a tremendous heterogeneity of GPC species produced enzymatically and even more via non-enzymatic processes which can exert PAFR agonistic effects ( 5 , 15 ). Moreover, some members of the PAF family of mediators include the 1-acyl species which are in much greater abundance than 1-alkyl GPC, yet have much lower binding affinities and have been suggested to act as antagonists ( 120 , 134 , 135 ). PAF is rapidly metabolized, with a half-life in biological fluids measured in minutes.…”

Plasmalogens, platelet-activating factor and beyond – Ether lipids in signaling and neurodegeneration

“…The relatively low potency of many species suggests a function in fine-tuning of responses possibly preventing ex-cessive activation by other, more potent ligands. Interestingly, the converse situation is true for PAF, itself a highly powerful mediator, with a much less potent acyl-analogue ascribed modulatory activity ( Chaithra et al, 2018 ). Future analyses with state-of-the-art methodology will undoubtedly allow the generation of additional quantitative data on the levels of less abundant ether lipid classes, thus facilitating interpretation and evaluation of their role in vivo .…”

AHistoplasma capsulatumlipid metabolic map identifies antifungal targets

“…Besides being water soluble, it is also possible that the H. capsulatum PAF analogs are being delivered to the host via extracellular vesicles secreted by this fungus (Albuquerque et al, 2008;Cleare et al, 2020). Endogenous acyl-PAF from mice has some PAF receptor agonistic effects in lower concentrations, but can become antagonists depending on the concentration and physiological condition (Chaithra et al, 2018).…”