Neutrophil Immunomodulatory Activity of Nerolidol, a Major Component of Essential Oils from <i>Populus balsamifera</i> Buds and Propolis

Propolis is a resinous mixture of substances collected and processed from various botanical sources by honeybees. Black poplar (<i>Populus balsamifera</i> L.) buds are one of the primary sources of propolis. Despite their reported therapeutic properties, little is known about the innate immunomodulatory activity of essential oils from <i>P. balsamifera</i> and propolis. In the present studies, essential oils were isolated from the buds of <i>P. balsamifera</i> and propolis collected in Montana. The main components of the essential oil from <i>P. balsamifera</i> were <i>E</i>-nerolidol (64.0%), 1,8-cineole (10.8%), benzyl benzoate (3.7%), α-terpinyl acetate (2.7%), α-pinene (1.8%), o-methyl anisol (1.8%), salicylaldehyde (1.8%), and benzyl salicylate (1.6%). Likewise, the essential oil from propolis was enriched with <i>E</i>-nerolidol (14.4%), cabreuva oxide-VI (7.9%), α-bisabolol (7.1%), benzyl benzoate (6.1%), β-eudesmol (3.6%), T-cadinol (3.1%), 2-methyl-3-buten-2-ol (3.1%), α-eudesmol (3.0%), fokienol (2.2%), nerolidol oxide derivative (1.9%), decanal (1.8%), 3-butenyl benzene (1.5%), 1,4-dihydronaphthalene (1.5%), selina-4,11-diene (1.5%), α-cadinol (1.5%), linalool (1.4%), γ-cadinene (1.4%), 2-phenylethyl-2-methyl butyrate (1.4%), 2-methyl-2-butenol (1.3%), octanal (1.1%), benzylacetone (1.1%), and eremoligenol (1.1%). A comparison between <i>P. balsamifera</i> and propolis essential oils demonstrated that 22 compounds were found in both essential oil samples. Both were enriched in <i>E</i>-nerolidol and its derivatives, including cabreuva oxide VI and nerolidol oxides. <i>P. balsamifera</i> and propolis essential oils and pure nerolidol activated Ca²⁺ influx in human neutrophils. Since these treatments activated neutrophils, the essential oil samples were also evaluated for their ability to down-regulate the neutrophil responses to subsequent agonist activation. Indeed, treatment with <i>P. balsamifera</i> and propolis essential oils inhibited subsequent activation of these cells by the <i>N</i>-formyl peptide receptor 1 (FPR1) agonist <i>f</i>MLF and the FPR2 agonist WKYMVM. Likewise, nerolidol inhibited human neutrophil activation induced by <i>f</i>MLF (IC₅₀ = 4.0 μM) and WKYMVM (IC₅₀ = 3.7 μM). Pretreatment with the essential oils and nerolidol also inhibited human neutrophil chemotaxis induced by <i>f</i>MLF, again suggesting that these treatments down-regulated human neutrophil responses to inflammatory chemoattractants. Finally, reverse pharmacophore mapping predicted several potential kinase targets for nerolidol. Thus, our studies have identified nerolidol as a potential anti-inflammatory modulator of human neutrophils.