The 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl]-coumarin downmodulates the FcγR- and CR-mediated oxidative metabolism and elastase release in human neutrophils: Possible mechanisms underlying inhibition of the formation and release of neutrophil extracellular traps.

Abstract

In this study, we report the ability of a set of eight 3-phenylcoumarin derivatives bearing 6,7- or 5,7-dihydroxyl groups, free or acetylated, bound to the benzopyrone moiety, to modulate the effector functions of human neutrophils. In general, (i) 6,7-disubstituted compounds (5, 6, 19, 20) downmodulated the Fcγ receptor-mediated neutrophil oxidative metabolism more strongly than 5,7-disubstituted compounds (21, 22, 23, 24), and (ii) hydroxylated compounds (5, 19, 21, 23) downmodulated this neutrophil function more effectively than their acetylated counterparts (6, 20, 22, 24, respectively). Compounds 5 (6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl]-coumarin) and 19 (6,7-dihydroxy-3-[3',4'-dihydroxyphenyl]-coumarin) effectively downmodulated the neutrophil oxidative metabolism elicited via Fcγ and/or complement receptors. Compound 5 also downmodulated the immune complex-stimulated phagocytosis, degranulation of elastase, and production and release of neutrophil extracellular traps, as well as the human neutrophil chemotaxis towards n-formyl-methionyl-leucyl-phenylalanine, without altering the expression level of formyl peptide receptor type 1. Both compounds 5 and 19 did not impair the neutrophil capacity to recognize and kill Candida albicans. Docking calculations revealed that compounds 5 and 19 directly interacted with three catalytic residues - Gln-91, His-95, and Arg-239 - inside the myeloperoxidase active site. Together, these findings indicate that (i) inhibition of reactive oxygen species generation and degranulation of elastase are closely associated with downmodulation of release of neutrophil extracellular traps; and (ii) compound 5 can be a prototype for the development of novel immunomodulating drugs to treat immune complex-mediated inflammatory diseases.