Cannabinoids Inhibit Migration of Microglial-like Cells to the HIV Protein Tat

Journal of Neuroimmune Pharmacology - Tập 6 - Trang 566-577 - 2011
Daniel Fraga1, Erinn S. Raborn1, Gabriela A. Ferreira1, Guy A. Cabral1
1Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, USA

Tóm tắt

Microglia are a population of macrophage-like cells in the central nervous system (CNS) which, upon infection by the human immunodeficiency virus (HIV), secrete a plethora of inflammatory factors, including the virus-specified trans-activating protein Tat. Tat has been implicated in HIV neuropathogenesis since it elicits chemokines, cytokines, and a chemotactic response from microglia. It also harbors a β-chemokine receptor binding motif, articulating a mode by which it acts as a migration stimulus. Since select cannabinoids have anti-inflammatory properties, cross the blood–brain barrier, and target specific receptors, they have potential to serve as agents for dampening untoward neuroimmune responses. The aim of this study was to investigate the effect of select cannabinoids on the migration of microglial-like cells toward Tat. Using a mouse BV-2 microglial-like cell model, it was demonstrated that the exogenous cannabinoids Delta-9-tetrahydrocannabinol (THC) and CP55940 exerted a concentration-related reduction in the migration of BV-2 cells towards Tat. A similar inhibitory response was obtained when the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) was used. The CB2 receptor (CB2R) antagonist SR144528, but not the CB1 receptor (CB1R) antagonist SR141716A, blocked this inhibition of migration. Similarly, CB2R knockdown with small interfering RNA reversed the cannabinoid-mediated inhibition. In addition, the level of the β-chemokine receptor CCR-3 was reduced and its intracellular compartmentation was altered. These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like cell migration to Tat is linked functionally to the CB2R. Furthermore, the results indicate that activation of the CB2R leads to altered expression and compartmentation of the β-chemokine receptor CCR-3.

Tài liệu tham khảo

Albini A, Mitchell CD, Thompson EW, Seeman R, Martin GR, Wittek AE, Quinnan GV (1988) Invasive activity and chemotactic response to growth factors by Kaposi’s sarcoma cells. J Cell Biochem 36:369–376 Albini A, Benelli R, Giunciuglio D, Cai T, Mariani G, Ferrini S, Noonan DM (1998) Identification of a novel domain of HIV tat involved in monocyte chemotaxis. J Biol Chem 273:15895–15900 Banks WA, Robinson SM, Nath A (2005) Permeability of the blood-brain barrier to HIV-1 Tat. Exp Neurol 193:218–227 Benelli R, Mortarini R, Anichini A, Giunciuglio D, Noonan DM, Montalti S, Tacchetti C, Albini A (1998) Monocyte-derived dendritic cells and monocytes migrate to HIV-Tat RGD and basic peptides. AIDS 12:261–268 Benito C, Kim WK, Chavarria I, Hillard CJ, Mackie K, Tolon RM, Williams K, Romero J (2005) A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci 25:2530–2536 Benveniste EN (1998) Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 9:259–275 Berman NE, Marcario JK, Yong C, Raghavan R, Raymond LA, Joag SV, Narayan O, Cheney PD (1999) Microglial activation and neurological symptoms in the SIV model of NeuroAIDS: association of MHC-II and MMP-9 expression with behavioral deficits and evoked potential changes. Neurobiol Dis 6:486–498 Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237 Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254 Buttini M, Appel K, Sauter A, Gebicke-Haerter PJ, Boddeke HW (1996) Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat. Neuroscience 71:1–16 Cabral GA, Marciano-Cabral F (2005) Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukocyte Biol 78:1192–1197 Cabral GA, Staab A (2005) Effects on the immune system. Handb Exp Pharmacol 168:385–423 Chang HK, Gallo RC, Ensoli B (1995) Regulation of cellular gene expression and function by the human immunodeficiency virus type 1 Tat protein. J Biomed Sci 2:189–202 Chung H, Brazil MI, Soe TT, Maxfield FR (1999) Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer’s amyloid beta-peptide by microglial cells. J Biol Chem 274:32301–32308 D’Aversa TG, Yu KO, Berman JW (2004) Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. J Neurovirol 10:86–97 de Paulis A, De Palma R, Di Gioia L, Carfora M, Prevete N, Tosi G, Accolla RS, Marone G (2000) Tat protein is an HIV-1-encoded beta-chemokine homolog that promotes migration and up-regulates CCR3 expression on human Fc epsilon RI + cells. J Immunol 165:7171–7179 Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle RD (2005) Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation 2:29 Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC (1993) Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287 Gehrmann J (1996) Microglia: a sensor to threats in the nervous system? Res Virol 147:79–88 Gendelman HE, Persidsky Y, Ghorpade A, Limoges J, Stins M, Fiala M, Morrisett R (1997) The neuropathogenesis of the AIDS dementia complex. AIDS 11(Suppl A):S35–S45 Giulian D, Baker TJ, Shih LC, Lachman LB (1986) Interleukin 1 of the central nervous system is produced by ameboid microglia. J Exp Med 164:594–604 Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX 26:83–94 Horvath RJ, Nutile-McMenemy N, Alkaitis MS, DeLeo JA (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557–569 Kremlev SG, Roberts RL, Palmer C (2004) Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J Neuroimmunol 149:1–9 Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318 Leong SK, Ling EA (1992) Amoeboid and ramified microglia: their interrelationship and response to brain injury. Glia 6:39–47 Liu J, Louie S, Hsu W, Yu KM, Nicholas HB Jr, Rosenquist GL (2008) Tyrosine sulfation is prevalent in human chemokine receptors important in lung disease. Am J Respir Cell Mol Biol 38:738–743 Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL (2009) Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis 34:300–307 Murikinati S, Juttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, Ledent C, Zimmer A, Kalinke U, Schwaninger M (2010) Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J 24:788–798 Nath A, Conant K, Chen P, Scott C, Major EO (1999) Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 274:17098–17102 Neel N, Schutyser E, Sai J, Fan GH, Richmond A (2005) Chemokine receptor internalization and intracellular trafficking. Cytokine Growth Factor Rev 16:637–658 New DR, Maggirwar SB, Epstein LG, Dewhurst S, Gelbard HA (1998) HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem 273:17852–17858 Nowell KW, Pettit DA, Cabral WA, Zimmerman HW Jr, Abood ME, Cabral GA (1998) High-level expression of the human CB2 cannabinoid receptor using a baculovirus system. Biochem Pharmacol 55:1893–1905 Orsini MJ, Debouck CM, Webb CL, Lysko PG (1996) Extracellular human immunodeficiency virus type 1 Tat protein promotes aggregation and adhesion of cerebellar neurons. J Neurosci 16:2546–2552 Pearson VL, Rothwell NJ, Toulmond S (1999) Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: correlation with the progression of cell death. Glia 25:311–323 Pietr M, Kozela E, Levy R, Rimmerman N, Lin YH, Stella N, Vogel Z, Juknat A (2009) Differential changes in GPR55 during microglial cell activation. FEBS Lett 583:2071–2076 Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 24:224–237 Raborn ES, Cabral GA (2010) Cannabinoid inhibition of macrophage migration to the trans-activating (Tat) protein of HIV-1 is linked to the CB(2) cannabinoid receptor. J Pharmacol Exp Ther 333:319–327 Re MC, Vignoli M, Furlini G, Gibellini D, Colangeli V, Vitone F, La Placa M (2001) Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients. J Clin Virol 21:81–89 Romero-Sandoval EA, Horvath R, Landry RP, DeLeo JA (2009) Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain 5:25 Rostasy KM (2005) Inflammation and neuroaxonal injury in multiple sclerosis and AIDS dementia complex: implications for neuroprotective treatment. Neuropediatrics 36:230–239 Rotshenker S (2003) Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease. J Mol Neurosci 21:65–72 Vene R, Benelli R, Noonan DM, Albini A (2000) HIV-Tat dependent chemotaxis and invasion, key aspects of tat mediated pathogenesis. Clin Exp Metastasis 18:533–538 Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S (2001) The role of glial cells in Parkinson’s disease. Curr Opin Neurol 14:483–489 Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice AS (2007) Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain. Brain 130:2688–2702 Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405 Watson K, Edwards RJ (1999) HIV-1-trans-activating (Tat) protein: both a target and a tool in therapeutic approaches. Biochem Pharmacol 58:1521–1528 Zheng H, Loh HH, Law P-Y (2010) Agonist-selective signaling of G protein-coupled receptor: mechanisms and implications. IUBMB Life 62:112–119 Zimmermann N, Conkright J, Rothenberg M (1999) CC chemokine receptor-3 undergoes prolonged ligand-induced internalization. J Biol Chem 274:12611–12618