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The Toll-like receptor 7/8-ligand resiquimod (R-848) primes human neutrophils for leukotriene B₄, prostaglandin E₂ and platelet-activating factor biosynthesis

Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Quebec Research Center and Faculty of Medicine, Laval University, Québec, Canada

¹Correspondence: Centre de Recherche en Rhumatologie et Immunologie, CHUQ Research Center (CHUL) and Laval University, 2705, boul. Laurier, local T1–49, Québec, Canada, G1V 4G2, #46166. E-mail: pierre.borgeat{at}crchul.ulaval.ca

Toll-like receptors (TLR) recognize pathogen-associated molecular patterns and play important roles in the innate immune system. While single-stranded viral RNA is the natural ligand of TLR7/TLR8, the imidazoquinoline resiquimod (R-848) is recognized as a potent synthetic agonist of TLR7/TLR8. We investigated the effects of TLR7/8 activation on lipid mediator production in polymorphonuclear leukocytes exposed to R-848. Although R-848 had minimal effects by itself, it strongly enhanced leukotriene B₄ formation on subsequent stimulation by fMLP, platelet-activating factor, and the ionophore A23187. R-848 acted via TLR8 but not TLR7 as shown by the lack of effect of the TLR7-specific ligand imiquimod. Priming with R-848 also resulted in enhanced arachidonic acid release and platelet-activating factor formation following fMLP stimulation, as well as enhanced prostaglandin E₂ synthesis following the addition of arachidonic acid. Western blot analysis demonstrated that R-848 induced the phosphorylation of the cytosolic phospholipase A₂, promoted 5-lipoxygenase translocation and potently stimulated the expression of the type 2 cyclooxygenase. Bafilomycin A1, an inhibitor of endosomal acidification, efficiently inhibited all R-848-induced effects. These studies demonstrate that TLR8 signaling strongly promotes inflammatory lipid mediator biosynthesis and provide novel insights on innate immune response to viral infections.—Hattermann, K., Picard, S., Borgeat, M., Leclerc, P., Pouliot, M., Borgeat, P. The Toll-like receptor 7/8-ligand resiquimod (R-848) primes human neutrophils for leukotriene B₄, prostaglandin E₂ and platelet-activating factor biosynthesis.

Key Words: PMN • lipid mediators

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