Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1β (IL-1β) signalling

Abstract

Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis. Activation of cannabinoid receptors suppresses chronic inflammatory responses through the attenuation of pro-inflammatory mediators. Moreover, the endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous system). The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1β (interleukin-1β) associated signalling pathways and NSC biology, in order to develop therapeutical strategies on CNS diseases that may facilitate brain repair. NSCs express functional CB1 and CB2 cannabinoid receptors, DAGLα (diacylglycerol lipase α) and the NSC markers SOX-2 and nestin. We have investigated the role of CB1 and CB2 cannabinoid receptors in the control of NSC proliferation and in the release of immunomodulators [IL-1β and IL-1Ra (IL-1 receptor antagonist)] that control NSC fate decisions. Pharmacological blockade of CB1 and/or CB2 cannabinoid receptors abolish or decrease NSC proliferation, indicating a critical role for both CB1 and CB2 receptors in the proliferation of NSC via IL-1 signalling pathways. Thus the endocannabinoid system, which has neuroprotective and immunomodulatory actions mediated by IL-1 signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult NSCs, and this may be of therapeutic interest in the emerging field of brain repair.

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

“…Other findings suggest a proneurogenic effect of IL-1β (de la Mano et al, 2007;Xue et al, 2015). In previous studies from our group, we observed that genetic deletion of IL-1β increases basal proliferation of NSC (Garcia-Ovejero et al, 2013).…”

“…CB1 and CB2 receptor agonists increase IL-1β levels in NSCs (Garcia-Ovejero et al, 2013), and it may be that the effects of EPA on 2-AG and p38 MAPK induces IL-1β thereby increasing proliferation, whereas pharmacological blockade of CB1 or CB2 or knockout of IL-1β attenuates this response, potentially via preventing the activation of other MAPKs, such as MEK1/2. These results provide important new insights into the interaction between omega-3 PUFAs and endocannabinoid signalling and the subsequent cellular mechanisms by which omega-3 PUFAs exert their effects on neurogenesis.…”

“…The cytokine IL-1 has a complex interaction with the p38 MAPK pathway and endocannabinoid signalling in regulating NSC fate (Garcia-Ovejero et al, 2013;MolinaHolgado and Molina-Holgado, 2010;Vela et al, 2002). Furthermore, we have previously shown an intricate balance exists between DHA and EPA and the inflammasome (Mandhair et al, 2012).…”

Endocannabinoids drive the acquisition of an alternative phenotype in microglia

“…ECBs are produced by both immune cells and neural cells (Salzet et al, 2000;Freund et al, 2003) and they appear to fulfill a key role in neuroimmune networks (García-Ovejero et al, 2013;Hernangómez et al, 2014). The first goal of this study was to examine whether the synthesis of eCBs is altered in M2a or M2c alternative activated microglia.…”

Spinal cord injury induces a long-lasting upregulation of interleukin-1β in astrocytes around the central canal

“…is present at high levels during the development of the CNS at times of high proliferation and differentiation (Giulian et al, 1988;de la Mano et al, 2007), and still can be found in the adult brain neurogenic niches (Barkho et al, 2006;Kaneko et al, 2006;Kokovay et al, 2012). In addition, neural stem/precursor cells (NPCs) express receptors for this cytokine in vivo and in vitro (Ben-Hur et al, 2003;Koo and Duman, 2008;Kokovay et al, 2012;Wu et al, 2013) and IL-1b inhibits proliferation and modulates maturation and fate of NPCs (Vela et al, 2002;de la Mano et al, 2007;Wang et al, 2007;Goshen et al, 2008;Koo and Duman, 2008;Koo et al, 2010;Crampton et al, 2012;Garcia-Ovejero et al, 2013a;Ryan et al, 2013). Depending on the context, IL-1b also promotes gliogenesis and inhibits neurogenesis (Moore et al, 2009;Crampton et al, 2012;Green et al, 2012;Ryan et al, 2013;Wu et al, 2013) or prevents lineage progression, maintaining undifferentiated NSCs (Kokovay et al, 2012).…”