title: Leukotrienes target F-actin/cofilin-1 to enhance alveolar macrophage anti-fungal activity.
abstract: Candida albicans is the most common opportunistic fungal pathogen and causes local and systemic disease in immunocompromised patients. Alveolar macrophages (AMs) are pivotal for the clearance of C. albicans from the lung. Activated AMs secrete 5-lipoxygenase-derived leukotrienes (LTs), which in turn enhance phagocytosis and microbicidal activity against a diverse array of pathogens. Our aim was to investigate the role of LTB(4) and LTD(4) in AM antimicrobial functions against C. albicans and the signaling pathways involved. Pharmacologic and genetic inhibition of LT biosynthesis as well as receptor antagonism reduced phagocytosis of C. albicans when compared with untreated or WT controls. Conversely, exogenous LTs of both classes augmented base-line C. albicans phagocytosis by AMs. Although LTB(4) enhanced mainly mannose receptor-dependent fungal ingestion, LTD(4) enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C-δ (PKCδ) and PI3K but not PKCα and MAPK activation. Both LTs reduced activation of cofilin-1, whereas they enhanced total cellular F-actin; however, LTB(4) accomplished this through the activation of LIM kinases (LIMKs) 1 and 2, whereas LTD(4) did so exclusively via LIMK-2. Finally, both exogenous LTB(4) and LTD(4) enhanced AM fungicidal activity in an NADPH oxidase-dependent manner. Our data identify LTB(4) and LTD(4) as key mediators of innate immunity against C. albicans, which act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.
authors.affiliation: Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Morato-Marques
authors.affiliation: Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Campos
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Steve
authors.initials: S
authors.lastname: Kane
authors.affiliation: Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Rangel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Casey
authors.initials: C
authors.lastname: Lewis
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.affiliation: Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Eulji University School of Medicine, Seoul, 139-711, Republic of Korea.
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jancar
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, and. Electronic address: cserezan@med.umich.edu.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Serezani
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002176:Candida albicans / Q000276:immunology / Q000378:metabolism*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051338:Cofilin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000502:physiology*; D037181:Lectins, C-Type; D007975:Leukotriene B4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054461:Lim Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051745:Protein Kinase C-delta; D051381:Rats; D017208:Rats, Wistar; D000099181:Dectin-1
chemical_list: D000199:Actins; D051338:Cofilin 1; D048049:Extracellular Signal-Regulated MAP Kinases; D037181:Lectins, C-Type; D007975:Leukotriene B4; D054461:Lim Kinases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051745:Protein Kinase C-delta; D000099181:Dectin-1; C495811:Cfl1 protein, mouse; C495812:Cfl1 protein, rat