Abstract
BackgroundNeuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; however, this has yet to be tested in the brain. Lowering the consumption of n-6 PUFA is associated with a decreased risk of depression and AD in human observational studies. The purpose of this study was to investigate the inflammation-modulating effects of lowering dietary n-6 PUFA in the mouse hippocampus.MethodsC57BL/6 male mice were fed either an n-6 PUFA deprived (2% of total fatty acids) or an n-6 PUFA adequate (23% of total fatty acids) diet from weaning to 12 weeks of age. Animals then underwent intracerebroventricular surgery, in which lipopolysaccharide (LPS) was injected into the left lateral ventricle of the brain. Hippocampi were collected at baseline and following LPS administration (1, 3, 7, and 14 days). A microarray (n = 3 per group) was used to identify candidate genes and results were validated by real-time PCR in a separate cohort of animals (n = 5–8 per group).ResultsMice administered with LPS had significantly increased Gene Ontology categories associated with inflammation and immune responses. These effects were independent of changes in gene expression in any diet group. Results were validated for the effect of LPS treatment on astrocyte, cytokine, and chemokine markers, as well as some results of the diets on Ifrd2 and Mfsd2a expression.ConclusionsLPS administration increases pro-inflammatory and lipid-metabolizing gene expression in the mouse hippocampus. An n-6 PUFA deprived diet modulated inflammatory gene expression by both increasing and decreasing inflammatory gene expression, without impairing the resolution of neuroinflammation following LPS administration.
Highlights
Neuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD)
Irrespective of diet, 1 day following LPS administration exhibited more clustering of increased gene expression for genes related to inflammation and immune processes than day 3 post-surgery, including Fc receptor (Fcgr1) and various components of lymphocytic molecules (lymphocytic antigen 86 (Ly86) and Ly6a), cluster of signaling protein differentiation and enzymes (signal transducer and activator of transcription 1 (Stat1), receptor transporter protein 4 (Rtp4), 2′-5′ oligoadenylate synthetase-like 1 (Oasl2), ubiquitin-specific peptidase 18 (Usp18), genes related to cytokine and chemokine signaling (Irf7, Irf9), interferon-induced transmembrane protein 3 (Ifitm3), interferon-induced protein with tetratricopeptide repeats 1 (Ifit1), and Ccl12
Similar trends of high expression of some genes such as the astrocyte marker (Gfap) complement component 1 q sub component, beta polypeptide (C1qb), beta-2 microglobulin (B2m), and a gene associated with n-6 polyunsaturated fatty acids (PUFA) metabolism Cytosolic phospholipase A2 (cPLA2), group IVA (Pla2g4a), are presented at both 1 day and 3 days after LPS administration
Summary
Neuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; this has yet to be tested in the brain. Neuroinflammation is an active defensive process characterized by many reactions including the release of arachidonic acid (ARA; n-6 PUFA), and ARA-derived proinflammatory lipid mediators, which in turn regulate inflammatory genes. Studies in humans have suggested a proinflammatory role of n-6 PUFA in many brain disorders, such as AD and depression [18, 19]. Because n-6 PUFA-derived lipid mediators can act as both pro- and anti-inflammatory, it is unclear how dietary n-6 PUFA modulates neuroinflammation
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