title: Dietary abscisic acid ameliorates influenza-virus-associated disease and pulmonary immunopathology through a PPARγ-dependent mechanism.
abstract: The anti-inflammatory phytohormone abscisic acid (ABA) modulates immune and inflammatory responses in mouse models of colitis and obesity. ABA has been identified as a ligand of lanthionine synthetase C-like 2, a novel therapeutic target upstream of the peroxisome proliferator-activated receptor γ (PPARγ) pathway. The goal of this study was to investigate the immune modulatory mechanisms underlying the anti-inflammatory efficacy of ABA against influenza-associated pulmonary inflammation. Wild-type (WT) and conditional knockout mice with defective PPARγ expression in lung epithelial and hematopoietic cells (cKO) treated orally with or without ABA (100 mg/kg diet) were challenged with influenza A/Udorn (H3N2) to assess ABA's impact in disease, lung lesions and gene expression. Dietary ABA ameliorated disease activity and lung inflammatory pathology, accelerated recovery and increased survival in WT mice. ABA suppressed leukocyte infiltration and monocyte chemotactic protein 1 mRNA expression in WT mice through PPARγ since this effect was abrogated in cKO mice. ABA ameliorated disease when administered therapeutically on the same day of the infection to WT but not mice lacking PPARγ in myeloid cells. We also show that ABA's greater impact is between days 7 and 10 postchallenge when it regulates the expression of genes involved in resolution, like 5-lipoxygenase and other members of the 5-lipoxygenase pathway. Furthermore, ABA significantly increased the expression of the immunoregulatory cytokine interleukin-10 in WT mice. Our results show that ABA, given preventively or therapeutically, ameliorates influenza-virus-induced pathology by activating PPARγ in pulmonary immune cells, suppressing initial proinflammatory responses and promoting resolution.
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory (www.nimml.org), Virginia Bioinformatics Institute, Virginia Tech., Blacksburg, VA 24061, USA. rmagarzo@vt.edu
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.forename: Paul C
authors.initials: PC
authors.lastname: Roberts
authors.forename: Adria
authors.initials: A
authors.lastname: Carbo
authors.forename: Cristina
authors.initials: C
authors.lastname: Vives
authors.forename: William T
authors.initials: WT
authors.lastname: Horne
authors.forename: Sandra
authors.initials: S
authors.lastname: Genis
authors.forename: Binu
authors.initials: B
authors.lastname: Velayudhan
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
mesh_terms: D000040:Abscisic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D004032:Diet; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014779:Virus Replication
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D047495:PPAR gamma; D016753:Interleukin-10; D000040:Abscisic Acid