title: Cytosolic phospholipase A2α enhances mouse mortality induced by Pseudomonas aeruginosa pulmonary infection via interleukin 6.
abstract: Pseudomonas aeruginosa pulmonary infection is a leading cause of death in numerous diseases such as cystic fibrosis (CF). The host cytosolic phospholipase A2α (cPLA2α) releases lipid mediators that play an important role in the pathogenesis of diseases, but its role in lung injury induced by P. aeruginosa infection is still obscure. Using an animal model of P. aeruginosa lung infection, we showed that the CHA strain of P. aeruginosa was more potent than the PAK strain in inducing mouse mortality and lung injury, and that both mouse mortality and lung injury were reduced in cPLA2α(-/-) mice as compared to cPLA2α(+/+) mice. This was accompanied by decreased levels of IL6 but not other inflammatory cytokines (IL1β, KC and TNFα) in the bronchoalveolar lavage fluids (BALFs) of cPLA2α(-/-) mice. Given that CFTR(-/-) mice exhibit increased cPLA2α activation in the lung, the role of cPLA2α was further examined in this lung infection model. Compared to littermates, P. aeruginosa infection caused increased mortality in CFTR(-/-) mice with high IL6 levels in BALFs, which was attenuated by pharmacological inhibition of cPLA2α. In addition, compared to IL6(-/-) mice, an enhanced mortality was also observed in P. aeruginosa infected IL6(+/+) mice. Since alveolar macrophages (AMs) are the primary inflammatory cytokine source in the lung, murine AMs cell line (MH-S) were used to investigate the signalling pathways involved in this process. Incubation of MH-S cells with P. aeruginosa induced IL6 production, which was mediated by MAPKs ERK/p38 and was abolished by cPLA2α inhibitors. Furthermore, among cPLA2 downstream signalling pathways, only 15-lipoxygenase (15-LOX) and cyclooxygenase-2 (COX-2) were proven to participate in this P. aeruginosa-induced IL6 expression. Based on all these observations, we conclude that cPLA2α enhances P. aeruginosa-induced animal lethality in part via IL6 induction and that MAPKs ERK/p38, 15-LOX and COX-2 signalling pathways were involved in this process.
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillemot
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Medina
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Pernet
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leduc
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France.
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
authors.affiliation: Unit of Innate Defence & Inflammation, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France; INSERM U874, 25 rue Dr Roux, 75015 Paris, France. Electronic address: yongzheng.wu@pasteur.fr.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism*; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000145:classification / Q000502:physiology; D013045:Species Specificity; D015996:Survival Rate; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D015850:Interleukin-6; C081565:arachidonyltrifluoromethane; D001093:Arachidonate 15-Lipoxygenase; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2
keywords: Acute lung infection; Cytosolic phospholipase A2α (cPLA2α); IL6; Inflammation; Pseudomonas aeruginosa