2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV.
Chouinard. François F; Turcotte. Caroline C; Guan. Xiaochun X; Larose. Marie-Chantal MC; Poirier. Samuel S; Bouchard. Line L; Provost. Véronique V; Flamand. Louis L; Grandvaux. Nathalie N; Flamand. Nicolas N
Key Findings
- Nanomolar levels of 2‑AG or AA activate neutrophils to produce antimicrobial effectors that inhibit bacterial growth and viral infectivity.
- The antimicrobial action is mediated mainly by LTB4 signaling through the BLT1 receptor, not by cannabinoid receptors.
- Neutrophils release large amounts of α‑defensins and only trace amounts of LL‑37 when stimulated by 2‑AG or AA.
Practical Outcomes
- For biohackers, the data suggest that boosting 2‑AG or AA could theoretically enhance innate immune defenses, but the study does not provide dosing guidelines, safety data, or direct ways to increase these lipids in humans. The modest LL‑37 release means that simply taking LL‑37 supplements is unlikely to replicate the effect. Until more translational research is done, the finding is interesting but not ready for actionable protocols.
Summary
The study shows that two naturally occurring lipids, 2‑arachidonoyl‑glycerol (2‑AG) and arachidonic acid (AA), can quickly turn into a signaling molecule (LTB4) that makes neutrophils release antimicrobial proteins, including a tiny amount of the peptide LL‑37. The released substances can block the spread of common bacteria (E. coli, S. aureus) and viruses (HSV‑1, RSV) in lab tests. However, the effect depends on a specific receptor (BLT1) and not on the usual cannabinoid receptors, and the amount of LL‑37 produced is very low.
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.
Study Information
pubmed
2012
2012-12-12T00:00:00.000Z
10.1189/jlb.0412200
42
89