Docosahexaenoic acid prevents lipopolysaccharide‐induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization

Abstract

Recognition of lipopolysaccharide (LPS), the endotoxin of gram‐negative bacteria, by microglia occurs through its binding to specific receptors, cluster of differentiation 14 and toll‐like receptor‐4. LPS binding to these receptors triggers the synthesis of proinflammatory cytokines that coordinate the brain innate immune response to protect the CNS of the infection. Docosahexaenoic acid (DHA), a n‐3 polyunsaturated fatty acid highly incorporated in the brain, is a potent immunomodulator. In this study, we investigated whether DHA modulates LPS receptor localization and, as a consequence, LPS‐induced signaling pathway and proinflammatory cytokine production. We demonstrated that DHA, when added exogenously, is specifically enriched in membrane phospholipids, but not in raft lipids of microglial cells. DHA incorporation in membrane impaired surface presentation of LPS receptors cluster of differentiation 14 and toll‐like receptor‐4, but not their membrane subdomain localization. LPS‐induced nuclear factor kappa B activation was inhibited by DHA, hence, LPS‐induced proinflammatory cytokine synthesis of interleukin‐1β and tumor necrosis factor α was strongly attenuated. We suggest that DHA is highly anti‐inflammatory by targeting LPS receptor surface location, therefore reducing LPS action on microglia. This effect represents a new insight by which DHA modulates in the brain the expression of proinflammatory cytokines in response to bacterial product.

Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation

“…Because LiCl did not increase the concentration of its precursor, unesterified DHA, or iPLA 2 -VI activity, consistent with prior data ( 20,33 ), the increment may have arisen from enhanced 15-LOX activity. On the other hand, unesterified DHA likely is partitioned in different brain compartments [it is found in neurons and glia ( 41,42 )], as reported for unesterified AA ( 23 ), one of which may be the precursor to 17-OH-DHA. Increased 15-LOX activity is suggested by the increased 15-HETE in the rats fed the LiCl diet during high LPS exposure, because 15-HETE is generated from AA by the action of 15-LOX.…”

Reduced prostaglandin F2α release from blood mononuclear leukocytes after oral supplementation of ω3 fatty acids: the OmegAD study

“…Our study and current literature cannot resolve these issues but might serve as a starting point for research on proand anti-infl ammatory effects of prostaglandins. Moreover, whether the effect of 3 FA is on CD14, TLR4 or other parts of the receptor system for LPS or downstream remains to be settled ( 40 ).…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…Both in vivo and in vitro studies have reported antiinflammatory activities of DHA in the brain especially in microglia (Laye, 2010;Orr and Bazinet, 2008). At the cellular level, brain DHA modulates several proinflammatory signalling pathways in microglia such as TLR signalling and nucleotide-binding oligomerization domain protein (NOD) signalling (De Smedt-Peyrusse et al, 2008;Liu et al, 2012), inhibits JUNK , and reduces or blocks NF-kB signalling (De Smedt-Peyrusse et al, 2008;Orr et al, 2013). The inhibitory effect of DHA on proinflammatory signalling pathway could be mediated by both non-genomic and genomic effect.…”

“…The inhibitory effect of DHA on proinflammatory signalling pathway could be mediated by both non-genomic and genomic effect. Indeed, DHA influences membrane composition of microglial cells and the TLR4 positioning, decreasing the binding of its ligand LPS (De Smedt-Peyrusse et al, 2008). DHA also impairs the phospholipid raft assembly of EPA and DHA in the plasma membrane (Rockett et al, 2011;Ruth et al, 2009).…”

“…The anti-inflammatory activity of DHA could also derive from its direct effect on invading macrophages or microglia. Both in vitro and in vivo data highlight that DHA blocks invading macrophages and microglia activation and the signalling pathway (NF-kB) in the brain and spinal cord of several inflammatory rodents models (De Smedt-Peyrusse et al, 2008;Figueroa et al, 2012;Lim et al, 2013;Lu et al, 2013). Recent data highlight that in vitro DHA has not only anti-inflammatory activity but also promotes microglia to a M2 phenotype with increased Aβ42 phagocytosis (Hjorth et al, 2013).…”