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The Toll‐like receptor 7/8‐ligand resiquimod (R‐848) primes human neutrophils for leukotriene B 4 , prostaglandin E 2 and platelet‐activating factor biosynthesis
Author(s) -
Hattermann Kim,
Picard Serge,
Borgeat Mathieu,
Leclerc Patrick,
Pouliot Marc,
Borgeat Pierre
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7457com
Subject(s) - tlr7 , arachidonic acid , lipid signaling , platelet activating factor , toll like receptor , phospholipase a2 , innate immune system , chemistry , microbiology and biotechnology , platelet activation , leukotriene b4 , biology , receptor , biochemistry , platelet , inflammation , immunology , enzyme
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 B 4 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 E 2 synthesis following the addition of arachidonic acid. Western blot analysis demonstrated that R‐848 induced the phosphorylation of the cytosolic phospholipase A 2 α, 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 re‐siquimod (R‐848) primes human neutrophils for leuko‐triene B4, prostaglandin E2 and platelet‐activating factor biosynthesis. FASEB J. 21, 1575–1585 (2007)