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  • Microglia after activation can show prominently pro inflamma

    2021-09-17

    Microglia after activation can show prominently pro-inflammatory but also anti-inflammatory characteristics [46]. Although the ageing process is not a pathological process, many of the age-associated changes resemble those observed under pathological conditions. An increase number of pro-inflammatory microglia in ageing increases the susceptibility of old individuals to various neurodegenerative disorders. This apparent consequence of Pifithrin-α ageing is mostly ascribed to the pro-inflammatory state of microglia. A recent publication reported that AEA drives microglia from a pro-inflammatory towards a more anti-inflammatory state that is more phagocytic in nature [12]. We show that ageing led to an increased Pifithrin-α of two prominent pro-inflammatory cytokines; IL-1β and IL-6 in wild-type mice. This age-related increase was totally absent (IL-1β) or failed to reach the level of significance (IL-6) in FAAH−/− mice. Importantly, IL-1β level was already high in young FAAH−/− mice, which may suggest higher inflammation. A possible reason why IL-1β and IL-6 are differently affected by FAAH could be that IL-1β is secreted through a non-classical export mechanism, whereas IL-6 through the classical mechanism [47]. It is possible that anandamide differentially affects these secretory pathways. Alternatively, since IL-1β and IL-6 are produced in a premature form, it is possible that anandamide differentially affects their maturation process [48]. Although the enhanced size of the microglia and increased IL-1β levels suggest a pro-inflammatory change in the hippocampus of FAAH−/− mice, astroglial activity or the level of IL-6 was similar in the knockout line as in wild-type mice in the same age group. These findings suggest rather a deregulation of glial activities in FAAH−/− mice than the presence of generally enhanced pro-inflammatory processes. The reason for the different reactivities of astrocyte and microglia to the enhanced AEA levels could be the difference in their receptor profile. Although both astrocyte and microglia express TRPV1 [49], [50], a target of AEA, they substantially differ in the expression of cannabinoid receptors. Microglia express cannabinoid receptors in an activity-dependent manner, whereby CB2 receptor expression is significantly higher than the expression of CB1 receptors [51]. On the other hand, astrocyte expresses CB-like and CB1 receptors but probably not CB2 receptors [51]. FAAH−/− mice are resistant to carrageenan-induced hyperalgesia, which is mediated partly by CB2 but not by the CB1 receptor [52], underlining the importance of CB2 signalling in the influence of AEA on glial activity. Our finding does not exclude that under more inflammatory conditions than those in brain-ageing AEA may also influence astrocyte activities. Indeed, astrocytes of FAAH−/− mice were more responsive to amyloid-β as indicated by an increased production of pro-inflammatory cytokines [53]. Nevertheless, pharmacological blockade of FAAH did not change astrocyte reactivity [53].
    Conclusion The following is the supplementary data related to this article.
    Conflict of interest statement
    Acknowledgments This work was financed by the Deutsche Forschungsgemeinschaft, grants FOR926 (SP2 and CP2) and SFB 645 (TP B7), as well as a BONFOR grant O-178.0014 of the Medical Faculty of the University of Bonn. A.Z. is a member of the DFG Cluster of Excellence ImmunoSensation.
    Introduction Despite the fact that paracetamol is the irreplaceable over-the-counter analgesic, its cellular and molecular action remains poorly understood (Mallet and Eschalier, 2010). Recently, a new idea emerged that considered paracetamol as a pro-drug needed to be biotransformed by a two-steps metabolism (Högestätt et al., 2005). The first step consists in a hepatic deacetylation of paracetamol into para-aminophenol. The second step is the conjugation of para-aminophenol with arachidonic acid by the Fatty Acid Amide Hydrolase (FAAH) enzyme into AM404. The key role of FAAH has been highlighted by the demonstration that inhibition of this key enzyme by a genetic strategy (FAAH knockout mice) or a pharmacological approach (administration of PMSF, a FAAH inhibitor) suppressed the synthesis of AM404 after a systemic paracetamol administration (Högestätt et al., 2005). This metabolic pathway, especially the FAAH enzyme, have been shown to be crucial for the analgesic action of paracetamol (Barrière et al., 2013, Mallet et al., 2008, Mallet et al., 2010). However, these studies were conducted in naive animals. In the clinical setting, paracetamol is used in a pathological pain context, notably in nociceptive pain (Altman et al., 2007, Wegman et al., 2004). Different mechanisms may underlie the analgesic action of paracetamol depending upon the pain context. For example, we highlighted that different spinal serotonergic receptors were involved in paracetamol analgesia according to the nature of the noxious stimulus (Bonnefont et al., 2005). In different models of acute visceral pain in mice, Haller et al. (2006) and Soukupová et al. (2010) did not demonstrate a FAAH-dependent analgesic mechanism. Consequently, the first purpose of this paper was to study the involvement of FAAH on paracetamol action in a more relevant clinical context using an inflammatory mouse model submitted to thermal and mechanical stimuli to assess hyperalgesia. Genetic and pharmacological strategies were used to inhibit FAAH and to assess its involvement in the anti-hyperalgesic effect of paracetamol.