The peptidyl-prolyl isomerase Pin1 controls GM-CSF-induced priming of NADPH oxidase in human neutrophils and priming at inflammatory sites

• Published in: International immunopharmacology Vol. 137; p. 112425
• Main Authors: Boussetta, Tarek, Raad, Houssam, Bedouhene, Samia, Arabi Derkawi, Riad, Gougerot-Pocidalo, Marie-Anne, Hayem, Gilles, Dang, Pham My-Chan, El-Benna, Jamel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 20-08-2024; Elsevier
• Subjects: Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Cells, Cultured; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Human health and pathology; Humans; Immunology; Immunotherapy; Inflammation - immunology; Innate immunity; Life Sciences; NADPH oxidase, NOX2; NADPH Oxidases - metabolism; Naphthoquinones - pharmacology; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; NIMA-Interacting Peptidylprolyl Isomerase - metabolism; Pin1; Priming, ROS, Rheumatoid arthritis; Reactive Oxygen Species - metabolism; Rhumatology and musculoskeletal system; NADPH; PBS; Priming, ROS, Rheumatoid arthritis; Phox; PMA; Neutrophils; PiB; MPO; RA; PMN; SDS-PAGE; GM-CSF; NADPH oxidase, NOX2; NOX; ROS; OPZ; Pin1; HBSS; fMLP or fMLF; NADPH oxidase; Rheumatoid arthritis; Priming; NOX2
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112425

•GM-CSF induced the activation of the prolyl cis/trans isomerase Pin1 in human neutrophils.•Juglone and PiB, two Pin1 inhibitors dampens GM-CSF-induced priming of superoxide production by human neutrophils.•Neutrophils from synovial fluid of rheumatoid arthritis patients showed an increase in Pin1 activity and ROS generation.•Pin1 inhibitors inhibited ROS hyper-production of neutrophils from synovial fluid of rheumatoid arthritis patients.
The production of superoxide anions and other reactive oxygen species (ROS) by neutrophils is necessary for host defense against microbes. However, excessive ROS production can induce cell damage that participates in the inflammatory response. Superoxide anions are produced by the phagocyte NADPH oxidase, a multicomponent enzyme system consisting of two transmembrane proteins (gp91phox/NOX2 and p22phox) and four soluble cytosolic proteins (p40phox, p47phox, p67phox and the small G proteins Rac1/2). Stimulation of neutrophils by various agonists, such as the bacterial peptide formyl-Met-Leu-Phe (fMLF), induces NADPH oxidase activation and superoxide production, a process that is enhanced by the pro-inflammatory cytokines such as GM-CSF. The pathways involved in this GM-CSF-induced up-regulation or priming are not fully understood. Here we show that GM-CSF induces the activation of the prolyl cis/trans isomerase Pin1 in human neutrophils. Juglone and PiB, two selective Pin1 inhibitors, were able to block GM-CSF-induced priming of ROS production by human neutrophils. Interestingly, GM-CSF induced Pin1 binding to phosphorylated p47phox at Ser345. Neutrophils isolated from synovial fluid of patients with rheumatoid arthritis are known to be primed. Here we show that Pin1 activity was also increased in these neutrophils and that Pin1 inhibitors effectively inhibited ROS hyperproduction by the same cells. These results suggest that the prolyl cis/trans isomerase Pin1 may control GM-CSF-induced priming of ROS production by neutrophils and priming of neutrophils in synovial fluid of rheumatoid arthritis patients. Pharmacological targeting of Pin1 may be a valuable approach to the treatment of inflammation.