2-Arachidonoyl-glycerol- And Arachidonic Acid-Stimulated Neutrophils Release Antimicrobial Effectors Against E. Coli, S. Aureus, HSV-1, and RSV

J Leukoc Biol. 2013 Feb;93(2):267-76. doi: 10.1189/jlb.0412200. Epub 2012 Dec 12.

Abstract

The endocannabinoid 2-AG is highly susceptible to its hydrolysis into AA, which activates neutrophils through de novo LTB(4) biosynthesis, independently of CB activation. In this study, we show that 2-AG and AA stimulate neutrophils to release antimicrobial effectors. Supernatants of neutrophils activated with nanomolar concentrations of 2-AG and AA indeed inhibited the infectivity of HSV-1 and RSV. Additionally, the supernatants of 2-AG- and AA-stimulated neutrophils strongly impaired the growth of Escherichia coli and Staphylococcus aureus. This correlated with the release of a large amount (micrograms) of α-defensins, as well as a limited amount (nanograms) of LL-37. All the effects of AA and 2-AG mentioned above were prevented by inhibiting LTB(4) biosynthesis or by blocking BLT(1). Importantly, neither CB(2) receptor agonists nor antagonists could mimic nor prevent the effects of 2-AG, respectively. In fact, qPCR data show that contaminating eosinophils express ∼100-fold more CB(2) receptor mRNA than purified neutrophils, suggesting that CB(2) receptor expression by human neutrophils is limited and that contaminating eosinophils are likely responsible for the previously documented CB(2) expression by freshly isolated human neutrophils. The rapid conversion of 2-AG to AA and their subsequent metabolism into LTB(4) promote 2-AG and AA as multifunctional activators of neutrophils, mainly exerting their effects by activating the BLT(1). Considering that nanomolar concentrations of AA or 2-AG were sufficient to impair viral infectivity, this suggests potential physiological roles for 2-AG and AA as regulators of host defense in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / immunology
  • Anti-Infective Agents / metabolism*
  • Arachidonic Acid / immunology*
  • Arachidonic Acid / pharmacology
  • Arachidonic Acids / immunology*
  • Arachidonic Acids / pharmacology
  • Cell Line
  • Endocannabinoids / immunology*
  • Endocannabinoids / pharmacology
  • Escherichia coli / immunology*
  • Glycerides / immunology*
  • Glycerides / pharmacology
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Neutrophil Activation / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Respiratory Syncytial Viruses / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Staphylococcus aureus / immunology*

Substances

  • Anti-Infective Agents
  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Arachidonic Acid
  • glyceryl 2-arachidonate