Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells

Abstract

The complex process of microglial activation encompasses several functional activation states associated either with neurotoxic/antineurogenic or with neurotrophic/proneurogenic properties, depending mainly on the extent of activation and the nature of the activating stimuli. Several studies have demonstrated that acute exposure to the prototypical activating agent lipopolysaccharide (LPS) confers antineurogenic properties upon microglial cells. Acutely activated microglia ortheir conditioned media (CM) reduce neural stem progenitor cell (NPC) survival and prevent NPC differentiation into neurons. The present study tested the hypothesis that docosahexaenoic acid (DHA), a long-chain polyunsatured fatty acid (L-PUFA) with potent immunomodulatory properties, could dampen microglial proinflammatory functions and modulate their antineurogenic effect. We demonstrate that DHA dose dependently inhibits the synthesis of inflammatory products in activated microglia without inducing an alternative antiinflammatory phenotype. Among the possible DHA mechanisms of action, we propose the inhibition of p38 MAPK phosphorylation and the activation of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-γ. The attenuation of M1 proinflammatory phenotype has relevant consequences for the survival and differentiation of NPC, because DHA reverses the antineurogenic activities of conditioned media from LPS-activated microglia. Our study identifies new relevant potentially protective and proneurogenic functions of DHA, exerted through the modulation of microglial functions, that could be exploited to sustain or promote neuroregenerative processes in damaged/aged brain.

Long-term omega-3 supplementation modulates behavior, hippocampal fatty acid concentration, neuronal progenitor proliferation and central TNF-α expression in 7 month old unchallenged mice

“…Increased neurogenesis in the subgranular zone of the hippocampus in young mice (Valente et al, 2009), and in cell culture (Antonietta Ajmone-Cat et al, 2012), have previously been shown to occur with Ω-3 supplementation. This is likely to occur through increased BDNF levels (Jiang et al, 2009), while Ω-3 deprivation has previously been shown to decrease BDNF and phosphorylated CMP response element binding protein (pCREB) (Bhatia et al, 2011).…”

“…This is likely to predominantly occur through increased Ω-3 displacing Ω-6 from the common metabolic enzyme pathway leading to increased Ω-3 derived prostaglandins, leukotrienes, and thromboxanes which are less pro-inflammatory than their Ω-6 derived counterparts (Tassoni et al, 2008; Farooqui, 2009; Wall et al, 2010). Additionally, cell culture studies have demonstrated that Ω-3 down regulates the p38 MAPK signaling pathway resulting in decreased nitric oxide synthase, decreasing nitric oxide, TNF-α and prostaglandin E2 (Antonietta Ajmone-Cat et al, 2012). Furthermore, Ω-3 promotes the production of peroxisome proliferator-activated receptor (PPAR)-γ, which is known to regulate microglia and astrocyte cytokine production.…”

“…Current literature suggests that inappropriate microglia activation plays a key degenerative role in the progression of cognitive decline (Antonietta Ajmone-Cat et al, 2012; Czirr and Wyss-Coray, 2012). This study suggests that in an unchallenged mouse model, increased microglia number is not a major contributing factor and other mechanisms such as the promotion of neuronal progenitor proliferation and modulation of cytokine activity may be more significant.…”

Function and Dysfunction of Microglia during Brain Development: Consequences for Synapses and Neural Circuits

“…Interestingly, docosahexaenoic acid (DHA), one of the most abundant PUFAs in the brain and a potent immunomodulator, was shown to prevent LPS-induced cytokine production in microglia, by directly inhibiting the surface presentation of CD14 and TLR4 (De Smedt-Peyrusse et al, 2008). A growing literature provides evidence for a direct role of DHA in regulating microglial activity (Antonietta Ajmone-Cat et al, 2012; Chen et al, 2014; Chang et al, 2015; Baufeld et al, 2016; Hao et al, 2016; Hopperton et al, 2016; Tremblay et al, 2016). …”

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

“…It has been demonstrated that DHA inhibits p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, which consequently inhibits the expression of inflammatory molecules in microglia (Lu et al, 2013) as well as activating PPARγ to modulate microglial inflammatory response (Antonietta Ajimone-Cat et al, 2012). It is now known that such regulation comes not from DHA itself, but from its derivatives (Heras-Sandoval et al, 2016).…”