, 2010, Hsu et al ,

2008, Masumoto et al , 2006 and Sabba

, 2010, Hsu et al.,

2008, Masumoto et al., 2006 and Sabbah et al., 2009). Thus, NOD1 is more widely expressed than NOD2 and occurs in peripheral and cerebral tissues (Inohara et al., 1999), while NOD2 expression is largely restricted to monocytes (Ogura et al., 2001). In line with these findings, cytokine levels were generally higher after treatment with MDP + LPS, together with the highest corticosterone levels and the kynurenine/tryptophan ratio in this group 1 day post-treatment, pointing to a relationship between cytokine expression, corticosterone release check details and kynurenine formation. In contrast, the behavioral effects were tendentially more pronounced after treatment with FK565 ± LPS. These disparities may arise from differential interactions of NOD1 and NOD2 with TLR4 at the blood–brain interface. On the one hand, NOD1, but not NOD2, is expressed in the choroid plexus and

other circumventricular organs (Inohara et al., 1999), which may also account for the particular ability of FK565 to enhance circulating corticosterone. On the other hand, the cerebral effects of peripherally injected LPS may be mediated by TLR4 on CNS-resident cells and be independent of systemic cytokine effects (Chakravarty and Herkenham, 2005 and Murray et al., 2011). In addition, LPS is able to induce a transient rise of intracellular Gamma-secretase inhibitor calcium in microglial cells of the area postrema, while MDP is devoid of such an effect, again pointing to absent NOD2 expression at this circumventricular organ

(Wuchert et al., 2008). The current study shows that NOD1 and NOD2 activation alone has only minor effects on cytokine production and sickness behavior but potently synergizes with TLR4 stimulation in aggravating and prolonging illness. Analysis of the potential mechanisms led us to conclude that the aggravation of sickness is associated with enhanced production of proinflammatory cytokines in the periphery and brain, increased kynurenine formation and activation of immune responsive brain nuclei. Further studies are warranted to analyze whether NOD1 and TLR4 interact with each other primarily at the blood–brain interface while NOD2 and TLR4 synergism occurs primarily in hematopoietic cells. Under conditions of infection or an Adenosine imbalance in microbiota-host interaction, NLRs and TLRs are likely to be targeted in parallel by an expanded number of PRR agonists. It remains to be investigated whether the concentrations of endogenous PRR agonists occurring in infection give rise to a similar synergism of NLRs and TLRs as seen here with FK565, MDP and LPS. We propose that the interaction of NLRs and TLRs in boosting a multidimensional sickness response reflects an important immunological and neurobiological mechanism of protection from microbial invasion.

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