title: TLR8, but not TLR7, induces the priming of the NADPH oxidase activation in human neutrophils.
abstract: Neutrophils play a key role in host defense against invading pathogens by releasing toxic agents, such as ROS and antimicrobial peptides. Human neutrophils express several TLRs that recognize a variety of microbial motifs. The interaction between TLR and their agonists is believed to help neutrophils to recognize and to kill pathogens efficiently by increasing their activation, a process called priming. However, excessive activation can induce tissue injury and thereby, contribute to inflammatory disorders. Agonists that activate TLR7 and TLR8 induce priming of neutrophil ROS production; however, which receptor is involved in this process has not been elucidated. In this study, we show that the selective TLR8 agonist, CL075 (3M002), induced a dramatic increase of fMLF-stimulated NOX2 activation, whereas the selective TLR7 agonist, loxoribine, failed to induce any priming effect. Interestingly, CL075, but not loxoribine, induced the phosphorylation of the NOX2 cytosolic component p47phox on several serines and the phosphorylation of p38MAPK and ERK1/2. The inhibitor of p38MAPK completely blocked CL075-induced phosphorylation of p47phox Ser345. Moreover, CL075, but not loxoribine, induced the activation of the proline isomerase Pin1, and juglone, a Pin1 inhibitor, prevented CL075-mediated priming of fMLF-induced superoxide production. These results indicate that TLR8, but not TLR7, is involved in priming of human neutrophil ROS production by inducing the phosphorylation of p47phox and p38MAPK and that Pin1 is also involved in this process.
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Karama
authors: K
authors: Makni-Maalej
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Viviana
authors: V
authors: Marzaioli
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Tarek
authors: T
authors: Boussetta
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Sahra Amel
authors: SA
authors: Belambri
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Marie-Anne
authors: MA
authors: Gougerot-Pocidalo
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Margarita
authors: M
authors: Hurtado-Nedelec
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria.
authors: Pham My-Chan
authors: PM
authors: Dang
authors: *Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Paris, France ; Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Unité Fonctionnelle Dysfonctionnements Immunitaires, Paris, France; and Laboratoire de Biochimie Appliquée, Université Ferhat Abbas, Sétif, Algéria jamel.elbenna@inserm.fr.
authors: Jamel
authors: J
authors: El-Benna
mesh_terms: D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011804:Quinolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C551788:CL 075; D008562:Membrane Glycoproteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D011804:Quinolines; D017382:Reactive Oxygen Species; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D013844:Thiazoles; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D006151:Guanosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; C068562:loxoribine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C005134:juglone
keywords: NOX2; ROS; p47phox; phagocyte; proline isomerase