Uncoupling of interleukin‐6 from its signalling pathway by dietary n‐3‐polyunsaturated fatty acid deprivation alters sickness behaviour in mice

Abstract

Sickness behaviour is an adaptive behavioural response to the activation of the innate immune system. It is mediated by brain cytokine production and action, especially interleukin-6 (IL-6). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are highly incorporated in brain cells membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 PUFA brain level by dietary means impacts on lipopolysaccharide (LPS)-induced IL-6 production and sickness behaviour. Our results show that mice exposed throughout life to a diet containing n-3 PUFA (n-3/n-6 diet) display a decrease in social interaction that does not occur in mice submitted to a diet devoid of n-3 PUFA (n-6 diet). LPS induced high IL-6 plasma levels as well as expression of IL-6 mRNA in the hippocampus and cFos mRNA in the brainstem of mice fed either diet, indicating intact immune-to-brain communication. However, STAT3 and STAT1 activation, a hallmark of IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice as compared to n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6 knock-out (IL-6 KO) mice and failed to induce STAT3 activation in the brain of IL-6 KO mice. Altogether, these findings point to alteration in brain STAT3 as a key mechanism for the lack of effect of LPS on social interaction in mice fed with the n-6 PUFA diet. The relative deficiency of Western diets in n-3 PUFA could impact on behavioural aspects of the host response to infection.

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

“…In vivo, chronic dietary LC n-3 PUFA deficiency significantly affected microglia activity and increased the release of IL-6 and TNF-α in the blood of rat (McNamara et al, 2010) and in the hippocampus of mice at post-natal day 21 (Madore et al, 2014), which was not observed in the brain of adult and aged mice (Delpech et al, 2015c;Mingam et al, 2008;Moranis et al, 2012). Alternatively, both in vivo and in vitro studies have reported anti-inflammatory activities of LC n-3 PUFA in the brain especially in microglia (Laye, 2010;Orr and Bazinet, 2008) and currently supports: 1) a capacity to down-regulate the activity of proinflammatory transcription factors such as NF-κB, 2) an inhibitory role on the release of cytokines, such as interleukin IL-1β and TNF-α, from activated microglia, 3) an inhibitory action against the production of NO and PGE2 in response to microglia activation, 4) a beneficial action on membrane lipid composition, lipid rafts and membrane receptors incorporation such as TLR receptors, and 5) a capacity to elicit peripheral and central proresolutive processes by activating phagocytosis and promoting polarization of glial cells toward a M2-like phenotype.…”

Neuroinflammation and aging: influence of dietary n-3 polyunsaturated fatty acid

“…In vivo, chronic dietary n-3 PUFA deficiency significantly increased the production and release of IL-6 and TNFa in the blood (McNamara et al, 2010). In addition, mice exposed throughout life to a diet devoid of n-3 PUFAs displayed lower brain DHA level and higher LPSinduced IL-6 in the plasma and in the hippocampus (Mingam et al, 2008). With aging, IL-6 expression was increased in the cortex of both n-3 deficient and n-3 adequate mice while IL-10 expression was decreased with no effect of long term a-LNA deficient or enriched diet (Moranis et al, 2011) (figure 4).…”

Association of Cardiac Pro-Β-Type Natriuretic Peptide Levels with Metabolic Risk Factors in Young Obese Egyptian Patients: A Focus on Normotensive vs. Hypertensive Patients

“…The remainders were allowed to clot and sera were separated by centrifugation (3500 rpm, 20 min, 25°C) and used freshly for determination of serum levels of fasting glucose [12], Insulin [13] and the lipid profile (T-Chol [14], HDL-C [15] and TG (16)] were analyzed using Synchron CX5 autoanalyzer (Beckman, USA) and LDL-cholesterol levels were calculated by using the Falholt et al formula [17]. Also, pro-inflammatory markers; Tumor Necrosis Factor (TNF)-α [18], interleukin (IL)-6 [19] cleaved to the N-terminal-proBNP(NT-proBNP) and BNP upon ventricular myocyte stretch. In practice, there is increasing recognition of the importance of BNP in the pathophysiology, diagnosis, prognosis and treatment of left ventricular dysfunction in selected patient groups [22][23][24], and other studies have shown an association of proBNP with subclinical cardiovascular diseases [25,26].…”