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  • The recently de orphaned G protein coupled receptor GPCR GPR

    2021-11-30

    The recently de-orphaned G-protein coupled receptor (GPCR), GPR55, is activated endogenously by L-α-lysophosphatidylinositol (LPI), a lipid signaling molecule, as well as N-arachidonoyl glycine (NAGly) and numerous endo, phyto, and synthetic cannabinoids (Oka et al., 2007, Henstridge et al., 2010, Heynen-Genel et al., 2010, Fakhouri et al., 2017, Ryberg et al., 2007, Console-Bram et al., 2017). Due to its activation by a number of cannabinoid compounds, GPR55 is considered a candidate cannabinoid receptor. Signaling through GPR55 in peripheral tissues has possessed pro- and anti-inflammatory effects depending on cell type and cause of inflammation. Activation of GPR55 was found to increase neutrophil chemotaxis and recruitment, increase pro-inflammatory cytokine release from monocytes and natural killer (NK) cells, and is involved in intestinal inflammatory responses (Balenga et al., 2011, Chiurchiu et al., 2015, Lin et al., 2011, Staton et al., 2008). In contrast to these pro-inflammatory data, it was also found that GPR55 reduced the release of nerve growth factor on inflammation-activated mast cells and attenuated neuroinflammation and chronic pain from colitis induced by intracolonic administration of dinitrobenzenesulfonic Demethoxycurcumin (Cantarella et al., 2011, Borrelli et al., 2015). In the central nervous system (CNS), the endogenous agonist for GPR55 (LPI) showed neuroprotective effects after excitotoxic lesion in a microglial and GPR55-dependent manner (Kallendrusch et al., 2013). Furthermore, GPR55 mRNA expression in microglia is down-regulated after treatment with LPS or IFNγ, suggesting that GPR55 is involved in neuroinflammation (Pietr et al., 2009). Recent evidence has also suggested a significant role for GPR55 in the hippocampus in that GPR55 activation boosts neurotransmitter release and modulates synaptic plasticity in the hippocampal CA1 region (Hurst et al., 2017, Sylantyev et al., 2013). Importantly, expression of GPR55 has been found on both human and murine NSCs and administration of GPR55 agonists increased both NSC proliferation and differentiation along a neuronal lineage in vitro and in vivo (Hill et al., 2018). Of note, GPR55−/− animals displayed reduced rates of hippocampal NSC proliferation, survival, and neuronal differentiation, suggesting that GPR55 is a necessary facet of NSC physiology (Hill et al., 2018). However, the role GPR55 plays in immune responses within NSC niches has not been properly explored. In this work, we sought to determine the effects of GPR55 activation on human and murine hippocampal NSCs under inflammatory conditions. We show here that treatment with GPR55 agonist protects against reduced neuron formation caused by IL-1β in vitro and chronic, low-level systemic inflammation induced by LPS administration in vivo. Activation of GPR55 demonstrated neuroprotective regulation of inflammatory cytokine receptor mRNA expression in both human and murine NSC cultures after IL-1β exposure. On the contrary, GPR55−/− mice displayed increased expression of inflammatory cytokine mRNA in the hippocampus after 14 days of continuous LPS treatment as compared to C57BL/6 animals, suggesting an immune-regulatory role for GPR55. Thus, GPR55 may present a yet unrecognized therapeutic target for alleviation of negative consequences of chronic peripheral inflammation on hippocampal neurogenesis and associated cognitive and behavioral alterations.
    Methods
    Results
    Discussion Dysregulation of adult hippocampal neurogenesis is implicated in numerous pathological conditions including Alzheimer’s disease, HIV-1 associated neurocognitive disorder, virus- induced memory dysfunction, and depression (Mu and Gage, 2011, Okamoto et al., 2007, Garber et al., 2018, Mahar et al., 2014). A common trait of each of these conditions is a chronic upregulation of inflammatory mediators leading to a neuroinflammatory state. Recently, the cannabinoid system has been implicated in NSC physiology and protection during pathophysiological conditions (Rodrigues et al., 2017, Palazuelos et al., 2006, Avraham et al., 2014). A potential member of the cannabinoid family, GPR55, has also been shown to regulate NSC proliferation and neuronal differentiation (Hill et al., 2018), yet comprehensive studies regarding GPR55 activation on NSCs during insult with inflammatory mediators are lacking.