Saturated fatty acids activate microglia via Toll-like receptor 4/NF-κB signalling

Abstract

Diets rich in SFA have been implicated in Alzheimer's disease (AD). There is strong evidence to suggest that microglial activation augments the progression of AD. However, it remains uncertain whether SFA can initiate microglial activation and whether this response can cause neuronal death. Using the BV-2 microglial cell line and primary microglial culture, we showed that palmitic acid (PA) and stearic acid (SA) could activate microglia, as assessed by reactive morphological changes and significantly increased secretion of pro-inflammatory cytokines, NO and reactive oxygen species, which trigger primary neuronal death. In addition, the mRNA level of these pro-inflammatory mediators determined by RT-PCR was also increased by PA and SA. We further investigated the intracellular signalling mechanism underlying the release of pro-inflammatory mediators from PA-activated microglial cells. The present results showed that PA activated the phosphorylation and nuclear translocation of the p65 subunit of NF-kB. Furthermore, pyrrolidine dithiocarbamate, a NF-kB inhibitor, attenuated the production of pro-inflammatory mediators except for IL-6 in PA-stimulated microglia. Administration of anti-Toll-like receptor (TLR)4-neutralising antibody repressed PA-induced NF-kB activation and pro-inflammatory mediator production. In conclusion, the present in vitro study demonstrates that SFA could activate microglia and stimulate the TLR4/NF-kB pathway to trigger the production of pro-inflammatory mediators, which may contribute to neuronal death.

Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters

“…It is well established that SFAs play a role in infl ammatory signaling ( 10,12,58,59 ). However, the degree to which individual FAs activate pro-infl ammatory pathways remains somewhat controversial, as there has been at least one study to report that SFAs do not activate TLRs in vitro ( 60 ).…”

Role of orexin A signaling in dietary palmitic acid-activated microglial cells

“…High fat diet increases circulating pro-inflammatory cytokines released from microglial cells, resulting in hypothalamic neuroinflammation and neurodegeneration [12, 13]. Chronic intake of saturated fatty acids (SFA) such as palmitic acid (PA, C16:0), activate microglia to an M1 phenotype, eliciting the release of pro-inflammatory cytokines [14, 15]. High fat diets cause this response by activating nuclear translocation of microglial nuclear factor-kappa B (NFκB), initiating release of pro-inflammatory cytokines such as TNF-α and interleukin-6 (IL-6) [13-15].…”

“…High fat diets cause this response by activating nuclear translocation of microglial nuclear factor-kappa B (NFκB), initiating release of pro-inflammatory cytokines such as TNF-α and interleukin-6 (IL-6) [13-15]. Palmitic acid activates microglia through a toll like receptor 4 (TLR-4)-dependent pathway, inducing the release of TNF-α and IL-6 [14]. Further, microglia activated by SFA via TLR-4 induce neuronal cell death [14].…”

“…Palmitic acid activates microglia through a toll like receptor 4 (TLR-4)-dependent pathway, inducing the release of TNF-α and IL-6 [14]. Further, microglia activated by SFA via TLR-4 induce neuronal cell death [14]. Given the above findings on orexin action in microglia, orexin signaling might promote microglia switching to a protective M2 phenotype, protecting against palmitic acid induced inflammation.…”

26 Intestinal Dysbiosis Contributes to the Delayed Gastrointestinal Transit in High Fat Diet Fed Mice

“…24,25 A HFD can lead to increased TLR4 expression and signaling. 26 Moreover, saturated fatty acids such as palmitate, a major fatty acid in HFD, can activate TLR4 signaling, 27,28 and hyperlipidemia leads to TLR4-dependent renal damages. 29 The effects of HFD and LPS together on the enteric nervous system is not known.…”