Role of an indole-thiazolidiene PPAR pan ligand on actions elicited by G-protein coupled receptor activated neutrophils

• Published in: Biomedicine & pharmacotherapy Vol. 105; pp. 947 - 955
• Main Authors: Santin, José Roberto, Machado, Isabel Daufenback, Drewes, Carine C., de Vinci Kanda Kupa, Léonard, Soares, Rodrigo Marcondes, Cavalcanti, Danielle Maia, da Rocha Pitta, Ivan, Farsky, Sandra H.P.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2018
• Subjects: Chemotaxis; fMLP; Inflammation; Neutrophil-endothelial interactions; NF-κB; NF-κB; Inflammation; fMLP; Chemotaxis; Neutrophil-endothelial interactions
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.06.056

Local treatment with LYSO-7 impairs leukocyte-endothelial interactions evoked by fMLP stimulation in mesentery postcapillary venules of male Wistar rats. In vitro LYSO-7 treatment reduces membrane and gene expression of adhesion molecules CD62 L and CD18, impairs NFκB nuclear translocation and blocks the elevation of intracellular calcium induced by fMLP activation in neutrophils. In vitro LYSO-7 treatment also induces expression of PPARγ and β/δ by neutrophils. [Display omitted] •Local treatment with LYSO-7 reduced the leukocyte-endothelial interactions.•LYSO-7 treatment reduced nuclear translocation of NF-κB evoked by fMLP activation.•LYSO-7 treatment induced expression of PPARγ and PPARβδ by neutrophils.•LYSO-7 inhibited neutrophil chemotaxis and reduced levels of intracellular calcium.•LYSO-7 inhibited protein and gene expression of adhesion molecule expression. Neutrophils are the first line of defence during inflammatory processes; nevertheless, exacerbated influx and actions of neutrophils in terms of uncontrolled inflammation are harmful to the host. Hence, neutrophil activity is the target of drugs seeking to address undesired inflammation. Here, we investigated the mechanisms of action of a ligand of the three isoforms of peroxisome proliferator-activated receptors (PPAR; (5Z)-5-[(5-bromo-1H-indole-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione), dubbed LYSO-7, on neutrophils activated by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), an agonist of G-protein coupled receptors (GPCRs) that binds to membrane-formylated peptide and activates intracellular inflammation pathways. Neutrophils were collected from the peritoneal cavity of male Wistar rats four hours after oyster glycogen injection. Afterwards, the neutrophils were incubated with saline or LYSO-7 (1 or 10 μM, 30 min), washed and stimulated with fMLP (10−7 μM, 1 h). LYSO-7 treatment inhibited gene and protein expression of adhesion molecules, CD62 L and CD18, abolished adhesion of neutrophils to endothelial cells, impaired chemotaxis, blocked the enhancement of intracellular calcium levels, induced the expression of PPARγ as well as PPARβδ and reduced nuclear translocation of nuclear factor κB (NF-κB). Moreover, topical application of LYSO-7 (10 mM) prior to local application of fMLP (10−7 μM) diminished the in vivo leukocyte-endothelial interactions in the mesentery microcirculation of rats. Together, our data highlight the effectiveness of anti-inflammatory actions of LYSO-7 on neutrophils activated by GPCRs, depending, at least in part, on impaired of NF-κB activation and induction of PPAR expression.