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      Gamma-Linolenic and Stearidonic Acids Are Required for Basal Immunity in Caenorhabditis elegans through Their Effects on p38 MAP Kinase Activity

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      1 , 2 , 3 , 1 , 2 , 3 , *
      PLoS Genetics
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          Abstract

          Polyunsaturated fatty acids (PUFAs) form a class of essential micronutrients that play a vital role in development, cardiovascular health, and immunity. The influence of lipids on the immune response is both complex and diverse, with multiple studies pointing to the beneficial effects of long-chain fatty acids in immunity. However, the mechanisms through which PUFAs modulate innate immunity and the effects of PUFA deficiencies on innate immune functions remain to be clarified. Using the Caenorhabditis elegansPseudomonas aeruginosa host–pathogen system, we present genetic evidence that a Δ6-desaturase FAT-3, through its two 18-carbon products—gamma-linolenic acid (GLA, 18:3n6) and stearidonic acid (SDA, 18:4n3), but not the 20-carbon PUFAs arachidonic acid (AA, 20:4n6) and eicosapentaenoic acid (EPA, 20:5n3)—is required for basal innate immunity in vivo. Deficiencies in GLA and SDA result in increased susceptibility to bacterial infection, which is associated with reduced basal expression of a number of immune-specific genes—including spp-1, lys-7, and lys-2—that encode antimicrobial peptides. GLA and SDA are required to maintain basal activity of the p38 MAP kinase pathway, which plays important roles in protecting metazoan animals from infections and oxidative stress. Transcriptional and functional analyses of fat-3–regulated genes revealed that fat-3 is required in the intestine to regulate the expression of infection- and stress-response genes, and that distinct sets of genes are specifically required for immune function and oxidative stress response. Our study thus uncovers a mechanism by which these 18-carbon PUFAs affect basal innate immune function and, consequently, the ability of an organism to defend itself against bacterial infections. The conservation of p38 MAP kinase signaling in both stress and immune responses further encourages exploring the function of GLA and SDA in humans.

          Author Summary

          Polyunsaturated fatty acids are vital for optimal physiological functions, including immunity. Much of these effects are mediated by eicosanoids, which are metabolites of arachidonic acid (AA) and eicosapentaenoic acid (EPA). In mammals, PUFAs cannot be synthesized de novo. They are produced from essential dietary fatty acids, which are first converted to gamma-linolenic acid (GLA) and stearidonic acid (SDA) by a rate-limiting step catalyzed by a Δ6-desaturase, FADS2. Activity of FADS2 is impaired under numerous conditions—including aging, diabetes, stress, and smoking—and could lead to reduced production of GLA and SDA. In this study, we examined the effects of loss-of-function mutations in PUFA biosynthetic genes on the ability of C. elegans to survive infection by the Gram-negative human pathogen P. aeruginosa. We show that the enhanced pathogen susceptibility of the C. elegans Δ6-desaturase mutant fat-3 is associated with decreased basal expression of immunity genes and disrupted activity of the p38 MAP kinase. These defects could be fully restored when both GLA and SDA, but not AA or EPA, were added into the diets of fat-3 mutants, further supporting the conclusion that GLA and SDA are required for basal immunity in C. elegans.

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          Most cited references72

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          Common virulence factors for bacterial pathogenicity in plants and animals.

          A Pseudomonas aeruginosa strain (UCBPP-PA14) is infectious both in an Arabidopsis thaliana leaf infiltration model and in a mouse full-thickness skin burn model. UCBPP-PA14 exhibits ecotype specificity for Arabidopsis, causing a range of symptoms from none to severe in four different ecotypes. In the mouse model, UCBPP-PA14 is as lethal as other well-studied P. aeruginosa strains. Mutations in the UCBPP-PA14 toxA, plcS, and gacA genes resulted in a significant reduction in pathogenicity in both hosts, indicating that these genes encode virulence factors required for the full expression of pathogenicity in both plants and animals.
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            The lipoxygenase pathway.

            Lipid peroxidation is common to all biological systems, both appearing in developmentally and environmentally regulated processes of plants. The hydroperoxy polyunsaturated fatty acids, synthesized by the action of various highly specialized forms of lipoxygenases, are substrates of at least seven different enzyme families. Signaling compounds such as jasmonates, antimicrobial and antifungal compounds such as leaf aldehydes or divinyl ethers, and a plant-specific blend of volatiles including leaf alcohols are among the numerous products. Cloning of many lipoxygenases and other key enzymes within the lipoxygenase pathway, as well as analyses by reverse genetic and metabolic profiling, revealed new reactions and the first hints of enzyme mechanisms, multiple functions, and regulation. These aspects are reviewed with respect to activation of this pathway as an initial step in the interaction of plants with pathogens, insects, or abiotic stress and at distinct stages of development.
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              Membrane fluidity and its roles in the perception of environmental signals.

              Poikilothermic organisms are exposed to frequent changes in environmental conditions and their survival depends on their ability to acclimate to such changes. Changes in ambient temperature and osmolarity cause fluctuations in the fluidity of cell membranes. Such fluctuations are considered to be critical to the initiation of the regulatory reactions that ultimately lead to acclimation. The mechanisms responsible for the perception of changes in membrane fluidity have not been fully characterized. However, the analysis of genome-wide gene expression using DNA microarrays has provided a powerful new approach to studies of the contribution of membrane fluidity to gene expression and to the identification of environmental sensors. In this review, we focus on the mechanisms that regulate membrane fluidity, on putative sensors that perceive changes in membrane fluidity, and on the subsequent expression of genes that ensures acclimation to a new set of environmental conditions.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                November 2008
                November 2008
                21 November 2008
                : 4
                : 11
                : e1000273
                Affiliations
                [1 ]Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ]Department Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
                [3 ]Program in Immunology, Stanford University School of Medicine, Stanford, California, United States of America
                Fred Hutchinson Cancer Research Center, United States of America
                Author notes

                Conceived and designed the experiments: MN MWT. Performed the experiments: MN. Analyzed the data: MN. Wrote the paper: MN MWT.

                Article
                08-PLGE-RA-0629R3
                10.1371/journal.pgen.1000273
                2581601
                19023415
                ecd3e976-be40-4491-a878-f6183e9356b3
                Nandakumar, Tan. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 30 May 2008
                : 20 October 2008
                Page count
                Pages: 18
                Categories
                Research Article
                Immunology/Genetics of the Immune System
                Immunology/Immunity to Infections
                Immunology/Innate Immunity

                Genetics
                Genetics

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