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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

      1 , 2 , 3 , 1 , 2 , 3 , *
      PLoS Genetics
      Public Library of Science

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          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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          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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                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                November 2008
                November 2008
                21 November 2008
                : 4
                : 11
                : e1000273
                [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.

                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.
                : 30 May 2008
                : 20 October 2008
                Page count
                Pages: 18
                Research Article
                Immunology/Genetics of the Immune System
                Immunology/Immunity to Infections
                Immunology/Innate Immunity



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