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

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 cell membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 (also known as omega3) 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 the IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice than n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6-knockout (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.

In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain.

The P2X(7) receptor (P2X(7)R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X(7)R has a role in the release of biologically active proinflammatory cytokines such as IL-1 beta, IL-6 and TNFalpha. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X(7)R(-/-) mice produce less IL-1 beta compared to glial cells from brains of wild-type mice. This is not the case for TNFalpha and IL-6. Our results indicate a selective effect of the P2X7R gene deletion on release of IL-1 beta release but not of IL-6 and TNFalpha. In addition, we confirm that only microglial cells produce IL-1beta, and this release is dependent on P2X(7)R and ABC1 transporter. Because IL-1 beta is a key regulator of the brain cytokine network and P2X(7)R is an absolute requirement for IL-1 beta release, we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X(7)R(-/-) mice compared to wild-type mice. IL-1 beta and TNFalpha mRNAs were less elevated in the brain of P2X(7)R(-/-) than in the brain of wild-type mice in response to systemic LPS. These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli, which certainly applies also to cytokine-dependent alterations in brain functions including sickness behavior.

Cellular distribution of interleukin-1alpha-immunoreactivity after MPTP intoxication in mice.

In young rodents, peripheral injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a dopaminergic nigrostriatal denervation (during the first week after injection), followed by a spontaneous dopaminergic reinnervation. Sprouting from residual neurons has been proposed to account for this event. It has been shown that an inflammatory process takes place during striatal dopaminergic denervation but its consequences remain controversial. Some clues notably indicate that interleukin (IL)-1alpha may participate in MPTP-induced inflammation and promote recovery. We therefore studied the immunohistochemical localization of IL-1alpha expression in the striatum and ventral mesencephalon at different times (1, 3, 6, 16, and 30 days) after MPTP injection in mice. IL-1alpha-immunoreactivity (ir) was observed in striatum, substantia nigra pars compacta, and ventral tegmental area. Apart from a few localization in mesencephalic activated microglia, IL-1alpha was almost exclusively found in activated astrocytes. However, in the striatal parenchyma, another component of IL-1alpha-ir colocalized with tyrosine hydroxylase (TH)-ir, a marker for dopaminergic neurons. Moreover, some parenchymal TH-positive axons were also found to express the growth cone-associated protein (GAP)-43, a marker for axonal growth cones. In the striatum, IL-1alpha-ir was also detected in a non-astrocytic perivascular component, with a distribution similar to GAP-43-ir. IL-1alpha could thus directly or indirectly influence striatal reorganization after MPTP.

A role of IL-1 in MPTP-induced changes in striatal dopaminergic and serotoninergic transporter binding: clues from interleukin-1 type I receptor-deficient mice.

In mice, the MPTP-induced striatal dopaminergic denervation is followed by a spontaneous partial DAT recovery and by serotoninergic hyperinnervation. We show that IL-1RI-deficient mice have a higher DAT decrease in the ventromedial striatum after MPTP and a higher basal serotoninergic innervation of the whole striatum. These data point to a possible role of IL-1RI in the early MPTP-induced structural or functional remodeling of the nigrostriatal dopamine system.