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

• Published in: Free radical biology & medicine Vol. 115; pp. 421 - 435
• Main Authors: Andrade, Micássio F., Kabeya, Luciana M., Bortot, Leandro O., dos Santos, Gabriela B., Santos, Everton O.L., Albiero, Lucinéia R., Figueiredo-Rinhel, Andréa S.G., Carvalho, Camila A., Azzolini, Ana Elisa C.S., Caliri, Antonio, Pupo, Mônica T., Emery, Flavio S., Lucisano-Valim, Yara Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018
• Subjects: 3-phenylcoumarin; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Cells, Cultured; Coumarins - chemistry; Coumarins - pharmacology; Docking; Elastase; Extracellular Traps - metabolism; Humans; Immunomodulation; Myeloperoxidase; Neutrophil extracellular trap; Neutrophils - physiology; Oxidation-Reduction; Oxidative Stress - drug effects; Pancreatic Elastase - metabolism; Peroxidase - metabolism; Phagocytosis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Complement - metabolism; Receptors, IgG - metabolism; NADPH; Reactive oxygen species; fMLP; DMSO; FPR1; MTT; MPO; i-IC; CL-luc; LDH; MFI; FITC; ANOVA; ABAH; IC50; NHS; 3-PD; Myeloperoxidase; Docking; IC; Elastase; FIPI; HX1; PBS; HBSS-gel; SAAVNA; PMA; DAPI; PKC; CR; NETs; TNF-α; PE; ROS; 3-phenylcoumarin; Neutrophil extracellular trap; CL-lum; GPCR; HBSS; DPI; FcγR
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.12.012

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. [Display omitted] •3-PD 5 downmodulates neutrophil ROS generation, phagocytosis, and degranulation.•3-PD 5 downmodulates the production and release of neutrophil extracellular traps.•3-PD 5 downmodulates neutrophil chemotaxis towards fMLP but not FPR1 expression.•3-PD 5 is not cytotoxic to neutrophils and does not interfere with microbial killing.•3-PD 5 directly interacts with three catalytic residues of myeloperoxidase.