Abstract
Intermitted fasting and other forms of calorie restriction are increasingly demonstrated to exert potential health benefits. Interestingly, restricted feeding is also able to mitigate sickness in response to bacterial factors stimulating Toll-like receptor 4 (TLR4). However, little is known about how fasting modifies the activity of virus-associated molecular patterns. We therefore analyzed the impact of an intermittent fasting (IF) regimen on the immune and behavioral response to the TLR3 agonist and viral mimic polyinosinic:polycytidylic acid [Poly(I:C)] in mice. The effects of intraperitoneally injected Poly(I:C) (12 mg/kg) on plasma and cerebral cytokine expression and behavior (locomotion, exploration, and ingestion) were examined in male C57BL/6N mice under control conditions and following a 9 days period of intermittent (alternate day) fasting (IF). Poly(I:C) increased the circulating levels of cytokines (TNF-α, MCP-1, IL-6, IL-10, IFN-α, IFN-γ), an effect amplified by IF. In addition, IF aggravated sickness behavior in response to Poly(I:C), while cerebral cytokine expression was enhanced by application of Poly(I:C) in the absence of a significant effect of IF. Furthermore, IF augmented the expression of neuropeptide Y (NPY) mRNA in the hypothalamus and increased the plasma levels of corticosterone, while Poly(I:C) had little effect on these readouts. Our data show that IF does not abate, but exaggerates the immune and sickness response to the viral mimic Poly(I:C). This adverse effect of IF occurs despite increased hypothalamic NPY expression and enhanced plasma corticosterone. We therefore propose that the effects of IF on the immune and behavioral responses to viral and bacterial factors are subject to different neuronal and neuroendocrine control mechanisms.
Highlights
Stimulation of the peripheral immune system is known to bring along changes in brain function and behavior
When applied to the periphery, LPS evokes an immune reaction by binding to Toll-like receptor 4 (TLR4), which is a subgroup member of pattern recognition receptors (PRR) that are part of the innate immune system and contribute to the first-line immune response evoked by invading pathogens (Poltorak et al, 1998; Kawai and Akira, 2011)
Alike most PRRs, TLR4 is found on the surface of numerous immune cells, and its stimulation leads to elevated cytokine levels in the plasma of organisms exposed to LPS (Kawai and Akira, 2011)
Summary
Stimulation of the peripheral immune system is known to bring along changes in brain function and behavior. Alike most PRRs, TLR4 is found on the surface of numerous immune cells, and its stimulation leads to elevated cytokine levels in the plasma of organisms exposed to LPS (Kawai and Akira, 2011). Animals injected intraperitoneally (i.p.) with LPS show enhanced expression of cytokines within the brain and activation of the hypothalamic-pituitary-adrenal (HPA) axis as reflected by elevated circulating corticosterone (CORT) levels (Lenczowski et al, 1997; Farzi et al, 2015b; Mayerhofer et al, 2017). These findings attest to a close immune synergy of the periphery and brain. While some of the changes observed in the brain are adaptive physiological processes that help the individual to overcome infection, in humans elevated cytokine levels as well as circulating LPS were found to correlate with symptoms of depression and anxiety (Raison et al, 2006; Vogelzangs et al, 2016)
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