Advertisement

The microglial endocannabinoid system is similarly regulated by lipopolysaccharide and interferon gamma

Published:September 14, 2022DOI:https://doi.org/10.1016/j.jneuroim.2022.577971

      Highlights

      • Lipopolysaccharide (LPS) and interferon gamma (IFNγ) independently induce a pro-inflammatory phenotype in microglia.
      • LPS and IFNγ affect components of the endocannabinoid system, including receptors and metabolic enzymes.
      • Combinations of LPS and IFNγ had differential effects on the microglial endocannabinoid system.
      • Synthetic cannabinoids influenced the capacity of microglia to release nitric oxide following LPS and IFNγ stimulation.

      Abstract

      Perturbation of the endocannabinoid system can have profound effects on immune function and synaptic plasticity. Microglia are one of few cell types with a self-contained endocannabinoid system and are positioned at the interface between the immune system and the central nervous system. Past work has produced conflicting results with respect to the effects of pro-inflammatory conditions on the microglial endocannabinoid system. Thus, we systematically investigated the relationship between the concentration of two distinct pro-inflammatory stimuli, lipopolysaccharide and interferon gamma, on the abundance of components of the endocannabinoid system within microglia. Here we show that lipopolysaccharide and interferon gamma influence messenger RNA abundances of the microglial endocannabinoid system in a concentration-dependent manner. Furthermore, we demonstrate that the efficacy of different synthetic cannabinoid treatments with respect to inhibition of microglia nitric oxide release is dependent on the concentration and type of pro-inflammatory stimuli presented to the microglia. This indicates that different pro-inflammatory stimuli influence the capacity of microglia to synthesize, degrade, and respond to cannabinoids which has implications for the development of cannabinoid-based treatments for neuroinflammation.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Akira S.
        • Uematsu S.
        • Takeuchi O.
        Pathogen recognition and innate immunity.
        Cell. 2006; 124: 783-801https://doi.org/10.1016/j.cell.2006.02.015
        • Ashton J.C.
        • Glass M.
        The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration.
        Curr. Neuropharmacol. 2007; 5: 73-80https://doi.org/10.2174/157015907780866884
        • Bagher A.M.
        • Young A.P.
        • Laprairie R.B.
        • Toguri J.T.
        • Kelly M.E.M.
        • Denovan-Wright E.M.
        Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments.
        J. Neurosci. Res. 2020; 98: 2496-2509https://doi.org/10.1002/jnr.24716
        • Bal-Price A.
        • Brown G.C.
        Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity.
        J. Neurosci. 2001; 21: 6480-6491https://doi.org/10.1523/jneurosci.21-17-06480.2001
        • Benito C.
        • Núñez E.
        • Tolón R.M.
        • Carrier E.J.
        • Rábano A.
        • Hillard C.J.
        • Romero J.
        Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in Neuritic plaque-associated glia in Alzheimer’s disease brains.
        J. Neurosci. 2003; 23: 11136-11141https://doi.org/10.1523/jneurosci.23-35-11136.2003
        • Brown G.C.
        • Borutaite V.
        Nitric oxide inhibition of mitochondrial respiration and its role in cell death.
        Free Radic. Biol. Med. 2002; 33: 1440-1450https://doi.org/10.1016/S0891-5849(02)01112-7
        • Cabral G.A.
        • Marciano-Cabral F.
        Cannabinoid receptors in microglia of the central nervous system: immune functional relevance.
        J. Leukoc. Biol. 2005; 78: 1192-1197https://doi.org/10.1189/jlb.0405216
        • Callén L.
        • Moreno E.
        • Barroso-Chinea P.
        • Moreno-Delgado D.
        • Cortés A.
        • Mallol J.
        • Casadó V.
        • Lanciego J.L.
        • Franco R.
        • Lluis C.
        • Canela E.I.
        • McCormick P.J.
        Cannabinoid receptors CB1 and CB2 form functional Heteromers in brain.
        J. Biol. Chem. 2012; 287: 20851-20865https://doi.org/10.1074/jbc.M111.335273
        • Carlisle S.J.
        • Marciano-Cabral F.
        • Staab A.
        • Ludwick C.
        • Cabral G.A.
        Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation.
        Int. Immunopharmacol. 2002; 2: 69-82https://doi.org/10.1016/S1567-5769(01)00147-3
        • Cassano T.
        • Calcagnini S.
        • Pace L.
        • De Marco F.
        • Romano A.
        • Gaetani S.
        Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target.
        Front. Neurosci. 2017; 11: 30https://doi.org/10.3389/fnins.2017.00030
        • Chhor V.
        • Le Charpentier T.
        • Lebon S.
        • Oré M.-V.
        • Celador I.L.
        • Josserand J.
        • Degos V.
        • Jacotot E.
        • Hagberg H.
        • Sävman K.
        • Mallard C.
        • Gressens P.
        • Fleiss B.
        Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro.
        Brain Behav. Immun. 2013; 32: 70-85https://doi.org/10.1016/j.bbi.2013.02.005
        • Correa F.
        • Hernangómez M.
        • Mestre L.
        • Loría F.
        • Spagnolo A.
        • Docagne F.
        • Di Marzo V.
        • Guaza C.
        Anandamide enhances IL-10 production in activated microglia by targeting CB2 receptors: roles of ERK1/2, JNK, and NF-κB.
        Glia. 2010; 58: 135-147https://doi.org/10.1002/glia.20907
        • Correa F.
        • Hernangómez-Herrero M.
        • Mestre L.
        • Loría F.
        • Docagne F.
        • Guaza C.
        The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells.
        Brain Behav. Immun. 2011; 25: 736-749https://doi.org/10.1016/j.bbi.2011.01.020
        • Cravatt B.F.
        • Giang D.K.
        • Mayfield S.P.
        • Boger D.L.
        • Lerner R.A.
        • Gilula N.B.
        Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.
        Nature. 1996; 384: 83-87https://doi.org/10.1038/384083a0
        • Devane W.A.
        • Hanus L.
        • Breuer A.
        • Pertwee R.G.
        • Stevenson L.A.
        • Griffin G.
        • Gibson D.
        • Mandelbaum A.
        • Etinger A.
        • Mechoulam R.
        Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
        Science. 1992; 258: 1946-1949https://doi.org/10.1126/science.1470919
        • Di Marzo V.
        • Fontana A.
        • Cadas H.
        • Schinelli S.
        • Cimino G.
        • Schwartz J.C.
        • Piomelli D.
        Formation and inactivation of endogenous cannabinoid anandamide in central neurons.
        Nature. 1994; 372: 686-691https://doi.org/10.1038/372686a0
        • Eljaschewitsch E.
        • Witting A.
        • Mawrin C.
        • Lee T.
        • Schmidt P.M.
        • Wolf S.
        • Hoertnagl H.
        • Raine C.S.
        • Schneider-Stock R.
        • Nitsch R.
        • Ullrich O.
        The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells.
        Neuron. 2006; 49: 67-79https://doi.org/10.1016/j.neuron.2005.11.027
        • Felder C.C.
        • Briley E.M.
        • Axelrod J.
        • Simpson J.T.
        • Mackie K.
        • Devane W.A.
        Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction.
        Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 7656-7660https://doi.org/10.1073/pnas.90.16.7656
        • Green D.S.
        • Young H.A.
        • Valencia J.C.
        Current prospects of type II interferon γ signaling and autoimmunity.
        J. Biol. Chem. 2017; 292: 13925-13933https://doi.org/10.1074/jbc.R116.774745
        • Hanus L.
        • Breuer A.
        • Tchilibon S.
        • Shiloah S.
        • Goldenberg D.
        • Horowitz M.
        • Pertwee R.G.
        • Ross R.A.
        • Mechoulam R.
        • Fride E.
        HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.
        Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 14228-14233https://doi.org/10.1073/pnas.96.25.14228
        • Häusler K.G.
        • Prinz M.
        • Nolte C.
        • Weber J.R.
        • Schumann R.R.
        • Kettenmann H.
        • Hanisch U.-K.
        Interferon-γ differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages.
        Eur. J. Neurosci. 2002; 16: 2113-2122https://doi.org/10.1046/j.1460-9568.2002.02287.x
        • Heifets B.D.
        • Castillo P.E.
        Endocannabinoid signaling and long-term synaptic plasticity.
        Annu. Rev. Physiol. 2009; 71: 283-306https://doi.org/10.1146/annurev.physiol.010908.163149
        • Hernangómez M.
        • Mestre L.
        • Correa F.G.
        • Loría F.
        • Mecha M.
        • Iñigo P.M.
        • Docagne F.
        • Williams R.O.
        • Borrell J.
        • Guaza C.
        CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation.
        Glia. 2012; 60: 1437-1450https://doi.org/10.1002/glia.22366
        • Hillard C.J.
        Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol.
        Prostaglandins Other Lipid Mediat. 2000; 61: 3-18https://doi.org/10.1016/s0090-6980(00)00051-4
        • Hillard C.J.
        • Manna S.
        • Greenberg M.J.
        • DiCamelli R.
        • Ross R.A.
        • Stevenson L.A.
        • Murphy V.
        • Pertwee R.G.
        • Campbell W.B.
        Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1).
        J. Pharmacol. Exp. Ther. 1999; 289: 1427-1433
        • Horvath R.J.
        • Nutile-McMenemy N.
        • Alkaitis M.S.
        • De Leo J.A.
        Differential migration, LPS-induced cytokine, chemokine and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures.
        J. Neurochem. 2008; 107: 557-569https://doi.org/10.1111/j.1471-4159.2008.05633.x
        • Howlett A.C.
        The cannabinoid receptors.
        Prostaglandins Other Lipid Mediat. 2002; 68–69: 619-631https://doi.org/10.1016/s0090-6980(02)00060-6
        • Howlett A.C.
        Cannabinoid receptor signaling.
        Handb. Exp. Pharmacol. 2005; 53–79https://doi.org/10.1007/3-540-26573-2_2
        • Kenakin T.
        Allosteric agonist modulators.
        J. Recept. Signal Transduct. Res. 2007; 27: 247-259https://doi.org/10.1080/10799890701509000
        • Klawonn A.M.
        • Fritz M.
        • Castany S.
        • Pignatelli M.
        • Canal C.
        • Similä F.
        • Tejeda H.A.
        • Levinsson J.
        • Jaarola M.
        • Jakobsson J.
        • Hidalgo J.
        • Heilig M.
        • Bonci A.
        • Engblom D.
        Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons.
        Immunity. 2021; 54 (e6): 225-234
        • Koenigsknecht-Talboo J.
        • Landreth G.E.
        Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines.
        J. Neurosci. 2005; 25: 8240-8249https://doi.org/10.1523/jneurosci.1808-05.2005
        • Kotenko S.V.
        • Izotova L.S.
        • Pollack B.P.
        • Mariano T.M.
        • Donnelly R.J.
        • Muthukumaran G.
        • Cook J.R.
        • Garotta G.
        • Silvennoinen O.
        • Ihle J.N.
        • Pestka S.
        Interaction between the components of the interferon γ receptor complex (∗).
        J. Biol. Chem. 1995; 270: 20915-20921https://doi.org/10.1074/jbc.270.36.20915
        • Krasnow S.M.
        • Knoll J.G.
        • Verghese S.C.
        • Levasseur P.R.
        • Marks D.L.
        Amplification and propagation of interleukin-1β signaling by murine brain endothelial and glial cells.
        J. Neuroinflammation. 2017; 14: 133https://doi.org/10.1186/s12974-017-0908-4
        • Leweke F.M.
        Anandamide dysfunction in prodromal and established psychosis.
        Curr. Pharm. Des. 2012; 18: 5188-5193https://doi.org/10.2174/138161212802884843
        • Lourbopoulos A.
        • Grigoriadis N.
        • Lagoudaki R.
        • Touloumi O.
        • Polyzoidou E.
        • Mavromatis I.
        • Tascos N.
        • Breuer A.
        • Ovadia H.
        • Karussis D.
        • Shohami E.
        • Mechoulam R.
        • Simeonidou C.
        Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis.
        Brain Res. 2011; 1390: 126-141https://doi.org/10.1016/j.brainres.2011.03.020
        • Lu H.-C.
        • Mackie K.
        An introduction to the endogenous cannabinoid system.
        Biol. Psychiatry. 2016; 79: 516-525https://doi.org/10.1016/j.biopsych.2015.07.028
        • Lu H.-C.
        • Mackie K.
        Review of the endocannabinoid system.
        Biol. Psychiatry Cogn. Neurosci. Neuroimaging. 2021; 6: 607-615https://doi.org/10.1016/j.bpsc.2020.07.016
        • Lu Y.-C.
        • Yeh W.-C.
        • Ohashi P.S.
        LPS/TLR4 signal transduction pathway.
        Cytokine. 2008; 42: 145-151https://doi.org/10.1016/j.cyto.2008.01.006
        • Ma L.
        • Jia J.
        • Liu X.
        • Bai F.
        • Wang Q.
        • Xiong L.
        Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling.
        Biochem. Biophys. Res. Commun. 2015; 458: 92-97https://doi.org/10.1016/j.bbrc.2015.01.073
        • Malek N.
        • Popiolek-Barczyk K.
        • Mika J.
        • Przewlocka B.
        • Starowicz K.
        Anandamide, acting via CB2 receptors, alleviates LPS-induced neuroinflammation in rat primary microglial cultures.
        Neural Plast. 2015; 2015e130639https://doi.org/10.1155/2015/130639
        • Maresz K.
        • Carrier E.J.
        • Ponomarev E.D.
        • Hillard C.J.
        • Dittel B.N.
        Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli.
        J. Neurochem. 2005; 95: 437-445https://doi.org/10.1111/j.1471-4159.2005.03380.x
        • Marsicano G.
        • Lafenêtre P.
        Roles of the endocannabinoid system in learning and memory.
        Curr. Top. Behav. Neurosci. 2009; 1: 201-230https://doi.org/10.1007/978-3-540-88955-7_8
        • McCoy K.L.
        Interaction between cannabinoid system and toll-like receptors controls inflammation.
        Mediat. Inflamm. 2016; 2016e5831315https://doi.org/10.1155/2016/5831315
        • Mecha M.
        • Feliú A.
        • Carrillo-Salinas F.J.
        • Rueda-Zubiaurre A.
        • Ortega-Gutiérrez S.
        • de Sola R.G.
        • Guaza C.
        Endocannabinoids drive the acquisition of an alternative phenotype in microglia.
        Brain Behav. Immun. 2015; 49: 233-245https://doi.org/10.1016/j.bbi.2015.06.002
        • Mechoulam R.
        • Ben-Shabat S.
        • Hanus L.
        • Ligumsky M.
        • Kaminski N.E.
        • Schatz A.R.
        • Gopher A.
        • Almog S.
        • Martin B.R.
        • Compton D.R.
        Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
        Biochem. Pharmacol. 1995; 50: 83-90https://doi.org/10.1016/0006-2952(95)00109-d
        • Miller S.I.
        • Ernst R.K.
        • Bader M.W.
        LPS, TLR4 and infectious disease diversity.
        Nat. Rev. Microbiol. 2005; 3: 36-46https://doi.org/10.1038/nrmicro1068
        • Moncada S.
        • Higgs E.A.
        Molecular mechanisms and therapeutic strategies related to nitric oxide.
        FASEB J. 1995; 9: 1319-1330
        • Mulder J.
        • Zilberter M.
        • Pasquaré S.J.
        • Alpár A.
        • Schulte G.
        • Ferreira S.G.
        • Köfalvi A.
        • Martín-Moreno A.M.
        • Keimpema E.
        • Tanila H.
        • Watanabe M.
        • Mackie K.
        • Hortobágyi T.
        • de Ceballos M.L.
        • Harkany T.
        Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease.
        Brain. 2011; 134: 1041-1060https://doi.org/10.1093/brain/awr046
        • Nagamoto-Combs K.
        • Kulas J.
        • Combs C.K.
        A novel cell line from spontaneously immortalized murine microglia.
        J. Neurosci. Methods. 2014; 233: 187-198https://doi.org/10.1016/j.jneumeth.2014.05.021
        • Navarro G.
        • Morales P.
        • Rodríguez-Cueto C.
        • Fernández-Ruiz J.
        • Jagerovic N.
        • Franco R.
        Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders.
        Front. Neurosci. 2016; 10: 406https://doi.org/10.3389/fnins.2016.00406
        • Navarro G.
        • Borroto-Escuela D.
        • Angelats E.
        • Etayo Í.
        • Reyes-Resina I.
        • Pulido-Salgado M.
        • Rodríguez-Pérez A.I.
        • Canela E.I.
        • Saura J.
        • Lanciego J.L.
        • Labandeira-García J.L.
        • Saura C.A.
        • Fuxe K.
        • Franco R.
        Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.
        Brain Behav. Immun. 2018; 67: 139-151https://doi.org/10.1016/j.bbi.2017.08.015
        • Navarro G.
        • Varani K.
        • Reyes-Resina I.
        • Sánchez de Medina V.
        • Rivas-Santisteban R.
        • Sánchez-Carnerero Callado C.
        • Vincenzi F.
        • Casano S.
        • Ferreiro-Vera C.
        • Canela E.I.
        • Borea P.A.
        • Nadal X.
        • Franco R.
        Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1–CB2 Heteroreceptor complexes.
        Front. Pharmacol. 2018; 9: 632https://doi.org/10.3389/fphar.2018.00632
        • Nomura D.K.
        • Morrison B.E.
        • Blankman J.L.
        • Long J.Z.
        • Kinsey S.G.
        • Marcondes M.C.G.
        • Ward A.M.
        • Lichtman A.H.
        • Conti B.
        • Cravatt B.F.
        Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.
        Science. 2011; 334: 809-813https://doi.org/10.1126/science.1209200
        • Palazuelos J.
        • Aguado T.
        • Pazos M.R.
        • Julien B.
        • Carrasco C.
        • Resel E.
        • Sagredo O.
        • Benito C.
        • Romero J.
        • Azcoitia I.
        • Fernández-Ruiz J.
        • Guzmán M.
        • Galve-Roperh I.
        Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity.
        Brain. 2009; 132: 3152-3164https://doi.org/10.1093/brain/awp239
        • Pandey R.
        • Mousawy K.
        • Nagarkatti M.
        • Nagarkatti P.
        Endocannabinoids and immune regulation.
        Pharmacol. Res. 2009; 60: 85-92https://doi.org/10.1016/j.phrs.2009.03.019
        • Panikashvili D.
        • Mechoulam R.
        • Beni S.M.
        • Alexandrovich A.
        • Shohami E.
        CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition.
        J. Cereb. Blood Flow Metab. 2005; 25: 477-484https://doi.org/10.1038/sj.jcbfm.9600047
        • Papageorgiou I.E.
        • Lewen A.
        • Galow L.V.
        • Cesetti T.
        • Scheffel J.
        • Regen T.
        • Hanisch U.-K.
        • Kann O.
        TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ.
        Proc. Natl. Acad. Sci. 2016; 113: 212-217https://doi.org/10.1073/pnas.1513853113
        • Pertwee R.G.
        Pharmacology of cannabinoid receptor ligands.
        Curr. Med. Chem. 1999; 6: 635-664
        • Poltorak A.
        • He X.
        • Smirnova I.
        • Liu M.Y.
        • Van Huffel C.
        • Du X.
        • Birdwell D.
        • Alejos E.
        • Silva M.
        • Galanos C.
        • Freudenberg M.
        • Ricciardi-Castagnoli P.
        • Layton B.
        • Beutler B.
        Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
        Science. 1998; 282: 2085-2088https://doi.org/10.1126/science.282.5396.2085
        • Raetz C.R.H.
        • Whitfield C.
        Lipopolysaccharide Endotoxins.
        Annu. Rev. Biochem. 2002; 71: 635-700https://doi.org/10.1146/annurev.biochem.71.110601.135414
        • Ross R.A.
        • Brockie H.C.
        • Pertwee R.G.
        Inhibition of nitric oxide production in RAW264.7 macrophages by cannabinoids and palmitoylethanolamide.
        Eur. J. Pharmacol. 2000; 401: 121-130https://doi.org/10.1016/S0014-2999(00)00437-4
        • Sagredo O.
        • González S.
        • Aroyo I.
        • Pazos M.R.
        • Benito C.
        • Lastres-Becker I.
        • Romero J.P.
        • Tolón R.M.
        • Mechoulam R.
        • Brouillet E.
        • Romero J.
        • Fernández-Ruiz J.
        Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease.
        Glia. 2009; 57: 1154-1167https://doi.org/10.1002/glia.20838
        • Schroder K.
        • Hertzog P.J.
        • Ravasi T.
        • Hume D.A.
        Interferon-γ: an overview of signals, mechanisms and functions.
        J. Leukoc. Biol. 2004; 75: 163-189https://doi.org/10.1189/jlb.0603252
        • Stansley B.
        • Post J.
        • Hensley K.
        A comparative review of cell culture systems for the study of microglial biology in Alzheimer’s disease.
        J. Neuroinflammation. 2012; 9: 115https://doi.org/10.1186/1742-2094-9-115
        • Stella N.
        Endocannabinoid signaling in microglial cells.
        Neuropharmacology. 2009; 56: 244-253https://doi.org/10.1016/j.neuropharm.2008.07.037
        • Stella N.
        Cannabinoid and cannabinoid-like receptors in microglia, astrocytes and astrocytomas.
        Glia. 2010; 58: 1017-1030https://doi.org/10.1002/glia.20983
        • Stella N.
        • Schweitzer P.
        • Piomelli D.
        A second endogenous cannabinoid that modulates long-term potentiation.
        Nature. 1997; 388: 773-778https://doi.org/10.1038/42015
        • Viader A.
        • Ogasawara D.
        • Joslyn C.M.
        • Sanchez-Alavez M.
        • Mori S.
        • Nguyen W.
        • Conti B.
        • Cravatt B.F.
        A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation.
        eLife. 2016; 5e12345https://doi.org/10.7554/eLife.12345
        • Waksman Y.
        • Olson J.M.
        • Carlisle S.J.
        • Cabral G.A.
        The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells.
        J. Pharmacol. Exp. Ther. 1999; 288: 1357-1366
        • Wenger T.
        • Moldrich G.
        The role of endocannabinoids in the hypothalamic regulation of visceral function.
        Prostaglandins Leukot. Essent. Fatty Acids (PLEFA). 2002; 66: 301-307https://doi.org/10.1054/plef.2001.0353
        • Wheelock E.F.
        Interferon-like virus-inhibitor induced in human leukocytes by Phytohemagglutinin.
        Science. 1965; 149: 310-311https://doi.org/10.1126/science.149.3681.310
        • Woodhams S.G.
        • Sagar D.R.
        • Burston J.J.
        • Chapman V.
        The role of the endocannabinoid system in pain.
        Handb. Exp. Pharmacol. 2015; 227: 119-143https://doi.org/10.1007/978-3-662-46450-2_7
        • Yamamoto Y.
        • Harashima A.
        • Saito H.
        • Tsuneyama K.
        • Munesue S.
        • Motoyoshi S.
        • Han D.
        • Watanabe T.
        • Asano M.
        • Takasawa S.
        • Okamoto H.
        • Shimura S.
        • Karasawa T.
        • Yonekura H.
        • Yamamoto H.
        Septic shock is associated with receptor for advanced glycation end products ligation of LPS.
        J. Immunol. 2011; 186: 3248-3257https://doi.org/10.4049/jimmunol.1002253
        • Young A.P.
        • Denovan-Wright E.M.
        The dynamic role of microglia and the endocannabinoid system in neuroinflammation.
        Front. Pharmacol. 2022; 12
        • Young A.P.
        • Denovan-Wright E.M.
        Synthetic cannabinoids reduce the inflammatory activity of microglia and subsequently improve neuronal survival in vitro.
        Brain Behav. Immun. 2022; 105: 29-43https://doi.org/10.1016/j.bbi.2022.06.011
        • Young A.P.
        • Landry C.F.
        • Jackson D.J.
        • Wyeth R.C.
        Tissue-specific evaluation of suitable reference genes for RT-qPCR in the pond snail, Lymnaea stagnalis.
        PeerJ. 2019; 7e7888https://doi.org/10.7717/peerj.7888
        • Young A.P.
        • Adderley S.J.
        • Bagher A.M.
        • Denovan-Wright E.M.
        Protein-protein allosteric effects on cannabinoid receptor heteromer signaling.
        in: Laprairie R.B. Allosteric Modulation of G Protein-Coupled Receptors. Academic Press, 2022: 71-96https://doi.org/10.1016/B978-0-12-819771-4.00001-4
        • Zhang Y.
        • Chen K.
        • Sloan S.A.
        • Bennett M.L.
        • Scholze A.R.
        • O’Keeffe S.
        • Phatnani H.P.
        • Guarnieri P.
        • Caneda C.
        • Ruderisch N.
        • Deng S.
        • Liddelow S.A.
        • Zhang C.
        • Daneman R.
        • Maniatis T.
        • Barres B.A.
        • Wu J.Q.
        An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.
        J. Neurosci. 2014; 34: 11929-11947https://doi.org/10.1523/jneurosci.1860-14.2014
        • Zhao J.
        • Kong H.J.
        • Li H.
        • Huang B.
        • Yang M.
        • Zhu C.
        • Bogunovic M.
        • Zheng F.
        • Mayer L.
        • Ozato K.
        • Unkeless J.
        • Xiong H.
        IRF-8/interferon (IFN) consensus sequence-binding protein is involved in toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways.
        J. Biol. Chem. 2006; 281: 10073-10080https://doi.org/10.1074/jbc.M507788200