| Summary: | <i>Grindelia squarrosa</i> (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEO<sub>Fl</sub>) and leaves (GEO<sub>Lv</sub>) of <i>G. squarrosa</i> and evaluated the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of these essential oils revealed that the main components were α-pinene (24.7 and 23.2% in GEO<sub>Fl</sub> and GEO<sub>Lv</sub>, respectively), limonene (10.0 and 14.7%), borneol (23.4 and 16.6%), <i>p</i>-cymen-8-ol (6.1 and 5.8%), β-pinene (4.0 and 3.8%), bornyl acetate (3.0 and 5.1%), <i>trans</i>-pinocarveol (4.2 and 3.7%), spathulenol (3.0 and 2.0%), myrtenol (2.5 and 1.7%), and terpinolene (1.7 and 2.0%). Enantiomer analysis showed that α-pinene, β-pinene, and borneol were present primarily as (−)-enantiomers (100% enantiomeric excess (ee) for (−)-α-pinene and (−)-borneol in both GEO<sub>Fl</sub> and GEO<sub>Lv</sub>; 82 and 78% ee for (−)-β-pinene in GEO<sub>Fl</sub> and GEO<sub>Lv</sub>), while limonene was present primarily as the (+)-enantiomer (94 and 96 ee in GEO<sub>Fl</sub> and GEO<sub>Lv</sub>). <i>Grindelia</i> essential oils activated human neutrophils, resulting in increased [Ca<sup>2+</sup>]<sub>i</sub> (EC<sub>50</sub> = 22.3 µg/mL for GEO<sub>Fl</sub> and 19.4 µg/mL for GEO<sub>Lv</sub>). In addition, one of the major enantiomeric components, (−)-borneol, activated human neutrophil [Ca<sup>2+</sup>]<sub>i</sub> (EC<sub>50</sub> = 28.7 ± 2.6), whereas (+)-borneol was inactive. Since these treatments activated neutrophils, we also evaluated if they were able to down-regulate neutrophil responses to subsequent agonist activation and found that treatment with <i>Grindelia</i> essential oils inhibited 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, (−)-borneol inhibited FPR-agonist-induced Ca<sup>2+</sup> influx in neutrophils. <i>Grindelia</i> leaf and flower essential oils, as well as (−)-borneol, also inhibited <i>f</i>MLF-induced chemotaxis of human neutrophils (IC<sub>50</sub> = 4.1 ± 0.8 µg/mL, 5.0 ± 1.6 µg/mL, and 5.8 ± 1.4 µM, respectively). Thus, we identified (−)-borneol as a novel modulator of human neutrophil function.
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