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

Vyala Hanumanthareddy Chaithra, Shancy Petsel Jacob, Chikkamenahalli Lakshminarayana Lakshmikanth, Mosale Seetharam Sumanth, Kandahalli Venkataranganayaka Abhilasha, Chu Huang Chen, Anita Thyagarajan, Ravi P. Sahu, Jeffrey Travers, Thomas M. McIntyre, Kempaiah Kemparaju, Gopal Kedihithlu Marathe

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2063-2074
Number of pages12
JournalJournal of Lipid Research
Volume59
Issue number11
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

    Fingerprint

Keywords

  • PAF acetylhydrolase
  • PAF analogue
  • PAF-like lipids
  • platelet aggregation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Chaithra, V. H., Jacob, S. P., Lakshmikanth, C. L., Sumanth, M. S., Abhilasha, K. V., Chen, C. H., Thyagarajan, A., Sahu, R. P., Travers, J., McIntyre, T. M., Kemparaju, K., & Marathe, G. K. (2018). Modulation of inflammatory platelet-activating factor (PAF) receptor by the acyl analogue of PAF. Journal of Lipid Research, 59(11), 2063-2074. https://doi.org/10.1194/jlr.M085704