2‐Arachidonoyl‐glycerol‐ and arachidonic acid‐stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV‐1, and RSV

[摘要] Theendocannabinoid2‐AGishighlysusceptibletoitshydrolysisintoAA,whichactivatesneutrophilsthroughdenovoLTB4biosynthesis,independentlyofCBactivation.Inthisstudy,weshowthat2‐AGandAAstimulateneutrophilstoreleaseantimicrobialeffectors.Supernatantsofneutrophilsactivatedwithnanomolarconcentrationsof2‐AGandAAindeedinhibitedtheinfectivityofHSV‐1andRSV.Additionally,thesupernatantsof2‐AG‐andAA‐stimulatedneutrophilsstronglyimpairedthegrowthofEscherichiacoliandStaphylococcusaureus.Thiscorrelatedwiththereleaseofalargeamount(micrograms)ofα‐defensins,aswellasalimitedamount(nanograms)ofLL‐37.AlltheeffectsofAAand2‐AGmentionedabovewerepreventedbyinhibitingLTB4biosynthesisorbyblockingBLT1.Importantly,neitherCB2receptoragonistsnorantagonistscouldmimicnorpreventtheeffectsof2‐AG,respectively.Infact,qPCRdatashowthatcontaminatingeosinophilsexpress∼100‐foldmoreCB2receptormRNAthanpurifiedneutrophils,suggestingthatCB2receptorexpressionbyhumanneutrophilsislimitedandthatcontaminatingeosinophilsarelikelyresponsibleforthepreviouslydocumentedCB2expressionbyfreshlyisolatedhumanneutrophils.Therapidconversionof2‐AGtoAAandtheirsubsequentmetabolismintoLTB4promote2‐AGandAAasmultifunctionalactivatorsofneutrophils,mainlyexertingtheireffectsbyactivatingtheBLT1.ConsideringthatnanomolarconcentrationsofAAor2‐AGweresufficienttoimpairviralinfectivity,thissuggestspotentialphysiologicalrolesfor2‐AGandAAasregulatorsofhostdefenseinvivo...

[学科分类] 生理学

[关键词] leukotriene;cannabinoid receptor;endocannabinoid;eicosanoid;GPR55;5‐lipoxygenase