Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation

There is now a large body of data indicating that the cannabinoid receptor type 2 (CB2) is linked to a variety of immune events. This functional relevance appears to be most salient in the course of inflammation, a process during which there is an increased number of receptors that are available for activation. Studies aimed at elucidating signal transduction events resulting from CB2 interaction with its native ligands, and of the role of exogenous cannabinoids in modulating this process, are providing novel insights into the role of CB2 in maintaining a homeostatic immune balance within the host. Furthermore, these studies suggest that the CB2 may serve as a selective molecular target for therapeutic manipulation of untoward immune responses, including those associated with a variety of neuropathies that exhibit a hyperinflammatory component.

[1]  E. Onaivi Neuropsychobiological Evidence for the Functional Presence and Expression of Cannabinoid CB2 Receptors in the Brain , 2007, Neuropsychobiology.

[2]  T. Bonner,et al.  Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Racke Experimental Autoimmune Encephalomyelitis (EAE) , 2001, Current protocols in neuroscience.

[4]  V. Perry,et al.  [The evidence for primary axonal loss in multiple sclerosis]. , 2000, Revista de neurologia.

[5]  Li Zhu,et al.  Methanandamide increases COX‐2 expression and tumor growth in murine lung cancer , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Miller,et al.  Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. , 2003, The Journal of clinical investigation.

[7]  P. Mcgeer,et al.  Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid‐type CB2 receptor , 2003, British journal of pharmacology.

[8]  R. Chandra,et al.  Elevated Inflammatory Markers in a Group of Amyotrophic Lateral Sclerosis Patients from Northern India , 2008, Neurochemical Research.

[9]  T. Hamilton,et al.  Effects of bacterial lipopolysaccharide on protein synthesis in murine peritoneal macrophages: Relationship to activation for macrophage tumoricidal function , 1986, Journal of cellular physiology.

[10]  T. Freund,et al.  Brain monoglyceride lipase participating in endocannabinoid inactivation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Piomelli,et al.  Functional role of high-affinity anandamide transport, as revealed by selective inhibition. , 1997, Science.

[12]  S. Wahl,et al.  N-formylmethionyl peptides as chemoattractants for leucocytes. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[13]  G. Cabral,et al.  Cannabinoid receptors in microglia of the central nervous system: immune functional relevance , 2005, Journal of leukocyte biology.

[14]  J. Berman,et al.  A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein , 2006, Journal of Neuroimmunology.

[15]  S. Galiègue,et al.  Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. , 1995, European journal of biochemistry.

[16]  G. Cabral,et al.  delta-9-Tetrahydrocannabinol inhibits cell contact-dependent cytotoxicity of Bacillus Calmétte-Guérin-activated macrophages. , 1993, International journal of immunopharmacology.

[17]  D. Dickson,et al.  Neuropathological Diagnosis of Alzheimer’s Disease: A Perspective from Longitudinal Clinicopathological Studies , 1997, Neurobiology of Aging.

[18]  S. Galiègue,et al.  Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation. , 1998, Blood.

[19]  K. Mackie,et al.  Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration , 2003, The Journal of Neuroscience.

[20]  T. Klein,et al.  Marijuana, immunity and infection , 1998, Journal of Neuroimmunology.

[21]  N. Volkow,et al.  In vivo imaging of the brain cannabinoid receptor. , 2002, Chemistry and physics of lipids.

[22]  M. Herkenham,et al.  Cannabinoid receptor localization in brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[23]  N. Kaminski,et al.  Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. , 1994, Biochemical pharmacology.

[24]  J. Crow,et al.  The CB2 cannabinoid agonist AM‐1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset , 2006, Journal of neurochemistry.

[25]  T. Möller,et al.  Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival , 2005, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[26]  I. Galve-Roperh,et al.  R-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN-2) ameliorates experimental autoimmune encephalomyelitis and induces encephalitogenic T cell apoptosis: partial involvement of the CB(2) receptor. , 2006, Biochemical pharmacology.

[27]  T. Bonner,et al.  Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. , 2000, European journal of pharmacology.

[28]  C. Guaza,et al.  CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies , 2008, British journal of pharmacology.

[29]  C. Raine,et al.  Multiple Sclerosis: Remyelination in Acute Lesions , 1993, Journal of neuropathology and experimental neurology.

[30]  J. Chambers,et al.  The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1) , 2000, British journal of pharmacology.

[31]  H. Friedman,et al.  Modulation of Interleukin 2 Activity by Δ9-Tetrahydrocannabinol after Stimulation with Concanavalin A, Phytohemagglutinin, or Anti-CD3 Antibody , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[32]  S. Tauber,et al.  Immune control by endocannabinoids — New mechanisms of neuroprotection? , 2007, Journal of Neuroimmunology.

[33]  T. Hamilton,et al.  The cell biology of macrophage activation. , 1984, Annual review of immunology.

[34]  G. Cabral,et al.  Effects on the immune system. , 2005, Handbook of experimental pharmacology.

[35]  P. Casellas,et al.  Cannabinoid-receptor expression in human leukocytes. , 1993, European journal of biochemistry.

[36]  K. Mackie,et al.  A Glial Endogenous Cannabinoid System Is Upregulated in the Brains of Macaques with Simian Immunodeficiency Virus-Induced Encephalitis , 2005, The Journal of Neuroscience.

[37]  T. Bonner,et al.  Expression of the CB1 cannabinoid receptor in macrophage-like cells from brain tissue: immunochemical characterization by fusion protein antibodies , 1998, Journal of Neuroimmunology.

[38]  D. Deutsch,et al.  2-arachidonyl-glycerol stimulates nitric oxide release from human immune and vascular tissues and invertebrate immunocytes by cannabinoid receptor 1. , 2000, Pharmacological research.

[39]  C. Ali,et al.  Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation , 2007, Molecular and Cellular Neuroscience.

[40]  J. Schwartz,et al.  Formation and inactivation of endogenous cannabinoid anandamide in central neurons , 1994, Nature.

[41]  A. Howlett,et al.  Cellular signal transduction by anandamide and 2-arachidonoylglycerol. , 2000, Chemistry and physics of lipids.

[42]  G. Nowak,et al.  EEDQ, a tool for ex vivo measurement of occupancy of D-1 and D-2 dopamine receptors. , 1988, European journal of pharmacology.

[43]  A. Szallasi Vanilloid (capsaicin) receptors in health and disease. , 2002, American journal of clinical pathology.

[44]  T. Mitchison,et al.  Actin-Based Cell Motility and Cell Locomotion , 1996, Cell.

[45]  B. Löwenberg,et al.  Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol. , 2002, Blood.

[46]  D. Gibson,et al.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor. , 1992, Science.

[47]  C. Newton,et al.  Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. , 2001, European journal of pharmacology.

[48]  C. Hillard,et al.  Endocannabinoids in neuroimmunology and stress. , 2005, Current drug targets. CNS and neurological disorders.

[49]  A. Howlett,et al.  Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. , 1984, Molecular pharmacology.

[50]  A. Molleman,et al.  Cannabinoid signalling (review) , 2006 .

[51]  H. Heng,et al.  Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. , 1999, Brain research. Molecular brain research.

[52]  V. Marzo,et al.  Identification of Endocannabinoids and Related Compounds in Human Fat Cells , 2007, Obesity.

[53]  K. Mackie,et al.  GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current , 2008, Proceedings of the National Academy of Sciences.

[54]  J. Falck,et al.  Endothelium-derived 2-arachidonylglycerol: an intermediate in vasodilatory eicosanoid release in bovine coronary arteries. , 2005, American journal of physiology. Heart and circulatory physiology.

[55]  T. Klein,et al.  Immunosuppression by Marijuana and Components , 1991 .

[56]  A. Lackner,et al.  Perivascular Macrophages Are the Primary Cell Type Productively Infected by Simian Immunodeficiency Virus in the Brains of Macaques , 2001, The Journal of experimental medicine.

[57]  A. Howlett,et al.  Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. , 1986, Molecular pharmacology.

[58]  S. Munro,et al.  Molecular characterization of a peripheral receptor for cannabinoids , 1993, Nature.

[59]  C. Breivogel,et al.  Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. , 2000, Journal of neurochemistry.

[60]  R. Pertwee GPR55: a new member of the cannabinoid receptor clan? , 2007, British journal of pharmacology.

[61]  L. Petrocellis,et al.  Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. , 1999, European journal of biochemistry.

[62]  G. Cabral,et al.  Cannabinoid-mediated exacerbation of brain infection by opportunistic amebae , 2004, Journal of Neuroimmunology.

[63]  A. Howlett Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. , 1985, Molecular pharmacology.

[64]  G. Cabral,et al.  Cannabinoid inhibition of the processing of intact lysozyme by macrophages: evidence for CB2 receptor participation. , 1999, The Journal of pharmacology and experimental therapeutics.

[65]  G. Cabral,et al.  Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease , 1998, Journal of Neuroimmunology.

[66]  G. O'neill,et al.  Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. , 1995, Molecular pharmacology.

[67]  N. E. Buckley The peripheral cannabinoid receptor knockout mice: an update , 2008, British journal of pharmacology.

[68]  F. Mach,et al.  Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice , 2005, Nature.

[69]  G. Cabral Lipids as bioeffectors in the immune system. , 2005, Life sciences.

[70]  L. Greensmith,et al.  Increasing cannabinoid levels by pharmacological and genetic manipulation delays disease progression in SOD1 mice , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[71]  D. Baker,et al.  In silico patent searching reveals a new cannabinoid receptor. , 2006, Trends in pharmacological sciences.

[72]  S. Glaser,et al.  Opposing Actions of Endocannabinoids on Cholangiocarcinoma Growth , 2007, Journal of Biological Chemistry.

[73]  H. Hartung,et al.  Matrix Metalloproteinases Exhibit Different Expression Patterns in Inflammatory Demyelinating Diseases of the Central and Peripheral Nervous System , 1999, Annals of the New York Academy of Sciences.

[74]  C. Newton,et al.  Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo. , 1991, Journal of toxicology and environmental health.

[75]  M. Glass,et al.  Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain , 2007, Neuroscience Letters.

[76]  E. Benveniste Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis , 1997, Journal of Molecular Medicine.

[77]  B. Dewald,et al.  Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. , 1994, Advances in immunology.

[78]  D. Selkoe,et al.  The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease , 1998 .

[79]  K. Mackie,et al.  Cloning and molecular characterization of the rat CB2 cannabinoid receptor. , 2002, Biochimica et biophysica acta.

[80]  C. Newton,et al.  Delta 9-tetrahydrocannabinol treatment suppresses immunity and early IFN-gamma, IL-12, and IL-12 receptor beta 2 responses to Legionella pneumophila infection. , 2000, Journal of immunology.

[81]  S. Arata,et al.  Enhanced Growth of Legionella pneumophila in Tetrahydrocannabinol-Treated Macrophages , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[82]  P. Iribarren,et al.  Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. , 2004, Cellular & molecular immunology.

[83]  P. Sacerdote,et al.  The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro , 2005, Journal of Neuroimmunology.

[84]  D. Clemente,et al.  Cannabinoid CB1 and CB2 Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis , 2007, The Journal of Neuroscience.

[85]  B. Juel-Jensen Cannabis and recurrent herpes simplex. , 1972, British medical journal.

[86]  J. Kehrl Chemoattractant receptor signaling and the control of lymphocyte migration , 2006, Immunologic research.

[87]  P. Casellas,et al.  Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. , 1996, European journal of biochemistry.

[88]  N. Rothwell,et al.  Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide‐induced nitric oxide release in astrocyte cultures , 2002, Journal of neuroscience research.

[89]  R. Ross Anandamide and vanilloid TRPV1 receptors , 2003, British journal of pharmacology.

[90]  V. Lagente,et al.  Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. , 1997, European journal of pharmacology.

[91]  Xavier Alvarez,et al.  Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system , 2001, Glia.

[92]  C. Gerard,et al.  C5A anaphylatoxin and its seven transmembrane-segment receptor. , 1994, Annual review of immunology.

[93]  B. Martin,et al.  The Cannabinoid Delta-9-tetrahydrocannabinol Mediates Inhibition of Macrophage Chemotaxis to RANTES/CCL5: Linkage to the CB2 Receptor , 2008, Journal of Neuroimmune Pharmacology.

[94]  R. Ransohoff,et al.  The many roles of chemokines and chemokine receptors in inflammation. , 2006, The New England journal of medicine.

[95]  C. Breivogel,et al.  Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. , 2001, Molecular pharmacology.

[96]  G. Cabral,et al.  Delta‐9‐Tetrahydrocannabinol (THC), the Major Psychoactive Component of Marijuana, Exacerbates Brain Infection by Acanthamoeba , 2001, The Journal of eukaryotic microbiology.

[97]  A. Buriani,et al.  Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[98]  N. Davoust,et al.  The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis. , 2008, The Journal of biological chemistry.

[99]  M. Herkenham,et al.  Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. , 1994, The Journal of pharmacology and experimental therapeutics.

[100]  T. Hamilton,et al.  Molecular mechanisms of signal transduction in macrophages. , 1987, Immunology today.

[101]  Y. Yamamoto,et al.  Tetrahydrocannabinol inhibition of macrophage nitric oxide production. , 1996, Biochemical pharmacology.

[102]  Y. Jeon,et al.  Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. , 1996, Molecular pharmacology.

[103]  D. Deutsch,et al.  Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide. , 2001, Molecular pharmacology.

[104]  G. Mckhann,et al.  Diseases of the Nervous System , 1905, The Hospital.

[105]  A. Barbáchano,et al.  Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study , 2004, Synapse.

[106]  P. Anand,et al.  COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord , 2006, BMC neurology.

[107]  T. Bisogno,et al.  Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. , 1999, Biochemical and biophysical research communications.

[108]  R. Blakely,et al.  Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. , 2000, The Journal of pharmacology and experimental therapeutics.

[109]  S. Smith,et al.  Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus , 1979, Infection and immunity.

[110]  Chang H. Kim Chemokine-chemokine receptor network in immune cell trafficking. , 2004, Current drug targets. Immune, endocrine and metabolic disorders.

[111]  H. Cottier,et al.  Distinct chemokinetic and chemotactic responses in neutrophil granulocytes , 1978, European journal of immunology.

[112]  P. Massi,et al.  Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)-tetrahydrocannabinol-induced inhibition of natural killer activity. , 2000, European journal of pharmacology.

[113]  G. Cabral,et al.  The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. , 1999, The Journal of pharmacology and experimental therapeutics.

[114]  M. Kano,et al.  Presynaptic Inhibition Caused by Retrograde Signal from Metabotropic Glutamate to Cannabinoid Receptors , 2001, Neuron.

[115]  R. Ramer,et al.  R(+)-methanandamide-induced cyclooxygenase-2 expression in H4 human neuroglioma cells: possible involvement of membrane lipid rafts. , 2004, Biochemical and biophysical research communications.

[116]  Shuxian Hu,et al.  Synthetic cannabinoid WIN55,212‐2 inhibits generation of inflammatory mediators by IL‐1β‐stimulated human astrocytes , 2005, Glia.

[117]  E. Goetzl,et al.  Specific binding of leukotriene B4 to receptors on human polymorphonuclear leukocytes. , 1982, Journal of immunology.

[118]  H. Harris Role of chemotaxis in inflammation. , 1954, Physiological reviews.

[119]  N. Kaminski,et al.  Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. , 1992, Molecular pharmacology.

[120]  M. Glass,et al.  The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. , 2007, Current neuropharmacology.

[121]  C. Breivogel,et al.  Levels, Metabolism, and Pharmacological Activity of Anandamide in CB1 Cannabinoid Receptor Knockout Mice , 2000 .

[122]  T. Freund,et al.  A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. , 2002, Chemistry and physics of lipids.

[123]  D. Hanahan Platelet activating factor: a biologically active phosphoglyceride. , 1986, Annual review of biochemistry.

[124]  J. Borrell,et al.  Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis , 2003, The Journal of Neuroscience.

[125]  G. Cabral,et al.  Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation. , 2001, Advances in experimental medicine and biology.

[126]  W. Campbell,et al.  Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. , 2004, Molecular pharmacology.

[127]  T. Ben-Hur,et al.  Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant , 1997, Journal of Neuroimmunology.

[128]  R. Watson Drugs of abuse and immune function , 1990 .

[129]  M. Fujiwara,et al.  New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. , 2004, Journal of pharmacological sciences.

[130]  N. Kaminski,et al.  Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system. , 1997, Toxicology and applied pharmacology.

[131]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[132]  P. Leigh,et al.  Motor neuron disease. , 1994, Springer London.

[133]  D. Kipmen-Korgun,et al.  Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. , 2003, British journal of pharmacology.

[134]  C. Velez-Pardo,et al.  Avoidance of Abeta[(25-35)] / (H(2)O(2)) -induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3K-dependent mechanisms: role of NF-kappaB and p53. , 2006, Medicinal chemistry.

[135]  M. Oz Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids. , 2006, Pharmacology & therapeutics.

[136]  T. Klein Cannabinoid-based drugs as anti-inflammatory therapeutics , 2005, Nature Reviews Immunology.

[137]  R. Ganju,et al.  Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. , 2006, Molecular immunology.

[138]  M. L. de Ceballos,et al.  Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation , 2005, The Journal of Neuroscience.

[139]  C. Newton,et al.  Downregulation of cannabinoid receptor 2 (CB2) messenger RNA expression during in vitro stimulation of murine splenocytes with lipopolysaccharide. , 2001, Advances in experimental medicine and biology.

[140]  Alberto Rábano,et al.  Cannabinoid CB2 Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer's Disease Brains , 2003, The Journal of Neuroscience.

[141]  G. Velasco,et al.  Cannabinoid CB2 receptor: a new target for controlling neural cell survival? , 2007, Trends in pharmacological sciences.

[142]  Yun Bai,et al.  Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation , 2005, Journal of Neuroinflammation.

[143]  C. Guaza,et al.  The endogenous cannabinoid anandamide potentiates interleukin‐6 production by astrocytes infected with Theiler's murine encephalomyelitis virus by a receptor‐mediated pathway , 1998, FEBS letters.

[144]  Z. Vogel,et al.  Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. , 1995, Biochemical pharmacology.

[145]  K. Waku,et al.  2-Arachidonoylglycerol Induces the Migration of HL-60 Cells Differentiated into Macrophage-like Cells and Human Peripheral Blood Monocytes through the Cannabinoid CB2 Receptor-dependent Mechanism* , 2003, Journal of Biological Chemistry.

[146]  J. Laitinen,et al.  Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. , 2004, Biochemical pharmacology.

[147]  G. Griffin,et al.  Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor. , 2000, The Journal of pharmacology and experimental therapeutics.

[148]  D. Kipmen-Korgun,et al.  Anandamide initiates Ca2+ signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells , 2003 .

[149]  K. Waku,et al.  2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells. , 2004, Journal of biochemistry.

[150]  B. Martin,et al.  Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. , 2002, Chemistry and physics of lipids.

[151]  P. Casellas,et al.  Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses. , 1999, The Journal of biological chemistry.

[152]  C. Murdoch,et al.  Chemokine receptors and their role in inflammation and infectious diseases. , 2000, Blood.

[153]  R. Watson,et al.  Influence of marijuana components (THC and CBD) on human mononuclear cell cytokine secretion in vitro. , 1991, Advances in experimental medicine and biology.

[154]  C. Newton,et al.  Δ9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-γ, IL-12, and IL-12 Receptor β2 Responses to Legionella pneumophila Infection1 , 2000, The Journal of Immunology.

[155]  S. Hjorth,et al.  The orphan receptor GPR55 is a novel cannabinoid receptor , 2007, British journal of pharmacology.

[156]  P. Sacerdote,et al.  In vivo and in vitro treatment with the synthetic cannabinoid CP55,940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors , 2000, Journal of Neuroimmunology.

[157]  Motor neuron disease. , 1994 .

[158]  G. Cabral,et al.  Delta-9-tetrahydrocannabinol inhibits macrophage protein expression in response to bacterial immunomodulators. , 1989, Journal of toxicology and environmental health.

[159]  S. Arata,et al.  Tetrahydrocannabinol treatment suppresses growth restriction of Legionella pneumophila in murine macrophage cultures. , 1991, Life sciences.

[160]  R. Price,et al.  Human immunodeficiency virus and the central nervous system. , 1992, Annual review of microbiology.

[161]  G. Uhl,et al.  Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain , 2006, Brain Research.

[162]  G. Cabral,et al.  Acanthamoeba spp. as Agents of Disease in Humans , 2003, Clinical Microbiology Reviews.

[163]  C. Newton,et al.  Cannabinoid receptors and immunity. , 1998, Immunology today.

[164]  D. Julius,et al.  Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide , 1999, Nature.

[165]  B Dewald,et al.  Human chemokines: an update. , 1997, Annual review of immunology.

[166]  E. Ponomarev,et al.  Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli , 2005, Journal of neurochemistry.

[167]  G. Cabral,et al.  CB2 receptors in the brain: role in central immune function , 2008, British journal of pharmacology.

[168]  P. Sonneveld,et al.  Distinct Expression Profiles of the Peripheral Cannabinoid Receptor in Lymphoid Tissues Depending on Receptor Activation Status 1 , 2004, The Journal of Immunology.

[169]  T. Groblewski,et al.  Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models , 2003, The European journal of neuroscience.

[170]  S. Miller,et al.  Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R(+)WIN55,212 , 2003 .

[171]  F. Entschladen,et al.  Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes , 2004, Cancer Immunology, Immunotherapy.

[172]  R. Ellis,et al.  Human immunodeficiency virus and the central nervous system. , 2006, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[173]  M. Herkenham,et al.  Cannabinoid receptor binding and messenger RNA expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains , 1994, Neuroscience.

[174]  D. Selkoe The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. , 1998, Trends in cell biology.

[175]  Z. Vogel,et al.  The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling , 1995, FEBS letters.

[176]  D Giulian,et al.  Characterization of ameboid microglia isolated from developing mammalian brain , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[177]  P. Casellas,et al.  Cannabinoids enhance human B‐cell growth at low nanomolar concentrations , 1995, FEBS letters.

[178]  T. Jin,et al.  Moving toward understanding eukaryotic chemotaxis. , 2006, European journal of cell biology.

[179]  C. Newton,et al.  Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection , 1994, Infection and immunity.

[180]  K. Mackie,et al.  Identification functional characterization of brainstem cannabinoid CB2 receptors. , 2022 .

[181]  D. Lauffenburger,et al.  Cell Migration: A Physically Integrated Molecular Process , 1996, Cell.

[182]  A. Arévalo-Martı́n,et al.  The endocannabinoid system modulates a transient TNF pathway that induces neural stem cell proliferation , 2008, Molecular and Cellular Neuroscience.

[183]  S. Mancham,et al.  Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. , 1997, Blood.

[184]  G. Cabral,et al.  Cannabinoids inhibit LPS‐inducible cytokine mRNA expression in rat microglial cells , 2000, Glia.

[185]  T. Bonner,et al.  Structure of a cannabinoid receptor and functional expression of the cloned cDNA , 1990, Nature.

[186]  E. S. Graham,et al.  Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal! , 2008, Journal of Neuroscience Methods.

[187]  G. Kreutzberg Microglia: a sensor for pathological events in the CNS , 1996, Trends in Neurosciences.

[188]  G. Cabral,et al.  Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. , 2002, International immunopharmacology.

[189]  G. Uhl,et al.  Discovery of the Presence and Functional Expression of Cannabinoid CB2 Receptors in Brain , 2006, Annals of the New York Academy of Sciences.