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 elegans–Pseudomonas 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.
Highlights
Polyunsaturated fatty acids (PUFAs) are a class of long chain fatty acids of 18 carbon atoms or more in length that contain two or more double bonds
Since the activity of lipid metabolism genes could be greatly influenced by available nutritional sources, and having determined that the fatty acid contents of E. coli and P. aeruginosa were different (Figure S1A), we quantified the mRNAs of elo and fat genes in worms exposed to PA14DgacA, an isogenic strain of P. aeruginosa PA14 in which the global virulence gene gacA, has been deleted [37]
Of the nine C. elegans genes known to be involved in the synthesis of the majority of 18- and 20-carbon PUFAs and monounsaturated fatty acids (MUFAs), fat-6, fat-2, fat-3 and fat-4 were expressed at higher levels in worms exposed to P. aeruginosa than to E. coli or PA14DgacA (Figure 1B)
Summary
Polyunsaturated fatty acids (PUFAs) are a class of long chain fatty acids of 18 carbon atoms or more in length that contain two or more double bonds. The 18-carbon and longer omega-6 and omega-3 PUFA families cannot be synthesized de novo They are produced, instead, from the dietary essential fatty acids linoleic acid (LA, 18:2n6) and alpha-linolenic acid (ALA, 18:3n3) through a series of desaturation and elongation reactions catalyzed by desaturase and elongase enzymes, respectively [1,2]. Omega-6 PUFAs, such as arachidonic acid (AA, 20:4n6) are converted into eicosanoids, leukotrienes and prostanoids through the actions of lipoxygenase and cyclooxygenase enzymes [3]. In vertebrates, these eicosanoids variously exert stimulatory and inhibitory influences and have profound effects on multiple aspects of organismal physiology, including immunity [4,5]. Instead of the 20-carbon AA, which is a minor PUFA in plants, 18-carbon PUFAs serve as Author Summary
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