Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1-TLR4-NF-κB pathway following experimental traumatic brain injuryReport as inadecuate




Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1-TLR4-NF-κB pathway following experimental traumatic brain injury - Download this document for free, or read online. Document in PDF available to download.

Journal of Neuroinflammation

, 14:143

First Online: 24 July 2017Received: 25 May 2017Accepted: 11 July 2017

Abstract

BackgroundMicroglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury TBI. High-mobility group box 1 HMGB1 protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products RAGE and toll-like receptors TLRs to activate downstream signaling pathways, such as the nuclear factor NF-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid ω-3 PUFA is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4-NF-κB signaling pathway are not clear.

MethodsThe Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor TNF-α, interleukin IL-1β, IL-6, interferon IFN-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4-NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI.

ResultsIt was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors TNF-α, IL-1β, IL-6, and IFN-γ, reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4-NF-κB signaling pathway.

ConclusionsThe results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1-TLR4-NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4-NF-κB signaling pathway, leading to neuroprotective effects.

KeywordsTraumatic brain injury Omega-3 polyunsaturated fatty acid Microglia Neuroinflammation HMGB1-TLR4-NF-κB pathway AbbreviationsELISAEnzyme-linked immunosorbent assay

HMGB1High-mobility group box 1

IFNInterferon

ILInterleukin

LPSLipopolysaccharide

mNSSModified neurological severity scores

NADNicotinamide adenine dinucleotide

NF-κBNuclear factor-κB

RAGEReceptor for advanced glycation end products

TBITraumatic brain injury

TLRsToll-like receptors

TNFTumor necrosis factor

ω-3 PUFAOmega-3 polyunsaturated fatty acid

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