Advertisement

Journal of Neuroimmune Pharmacology

, Volume 10, Issue 2, pp 302–308 | Cite as

Activation of Cannabinoid Type Two Receptors (CB2) Diminish Inflammatory Responses in Macrophages and Brain Endothelium

  • Yuri PersidskyEmail author
  • Shongshan Fan
  • Holly Dykstra
  • Nancy L. Reichenbach
  • Slava Rom
  • Servio H. Ramirez
BRIEF REPORT

Abstract

Chronic neuroinflammatory disorders (such as HIV associated neurodegeneration) require treatment that decreases production of inflammatory factors by activated microglia and macrophages and protection of blood brain barrier (BBB) injury secondary to activation of brain endothelium. Cannabioid type 2 receptor (CB2) is highly expressed on macrophages and brain microvasular enndothelial cells (BMVEC) and is upregulated in inflammation and HIV infection. It has been shown that CB2 activation dampened inflammatory responses in macrophages and BMVEC. In this study, we assessed by PCR array the expression of a wide range of genes increased in macrophages and BMVEC in inflammation. TNFα treatment upregulated 33 genes in primary human BMVEC, and two highly selective CB2 agonists diminished expression of 31 and 32 genes. These results were confirmed by functional assays (BBB protection after inflammatory insult and decreased migration of monocytes across BMVEC monolayers after CB2 stimulation). Similarly, CB2 stimulation in primary human macrophages led to the suppression of 35 genes out of the 50 genes upregulated by LPS. Such changes in gene expression paralleled diminished secretion of proinflammatory factors. These results indicate the potential utility of CB2 agonists for the treatment of neuroinflammation.

Keywords

Cannabinoid type 2 receptor Neuroinflammation Brain endothelial cell Macrophage Blood brain barrier 

Notes

Acknowledgments

The work is supported by grants from: MH65151 (YP), NIH/NIAAA, AA015913 (YP), NIH/NINDS, NS086570 (SHR), The Shriners Hospitals for Children 85110-PHI-14 (SHR), NIH/NIMH, and NIH/NINDS, NS087385 (SR).

Conflict of Interest

Authors declare no conflict of interests.

References

  1. Cross S, Onen N, Gase A, Overton ET, Ances BM (2013) Identifying risk factors for HIV-associated neurocognitive disorders using the international HIV dementia scale. J Neuroimmune Pharmacol 8:1114–1122PubMedCentralPubMedCrossRefGoogle Scholar
  2. Marcotte TD, Deutsch R, Michael BD, Franklin D, Cookson DR, Bharti AR, Grant I, Letendre SL, Group C (2013) A concise panel of biomarkers identifies neurocognitive functioning changes in HIV-infected individuals. J Neuroimmune Pharmacol 8:1123–1135PubMedCrossRefGoogle Scholar
  3. Buch SJ (2013) Cannabinoid receptor 2 activation: a means to prevent monocyte-endothelium engagement. Am J Pathol 183:1375–1377PubMedCrossRefGoogle Scholar
  4. Purohit V, Rapaka RS, Rutter J (2014) Cannabinoid receptor-2 and HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol 9:447–453PubMedCrossRefGoogle Scholar
  5. Molina PE, Amedee A, LeCapitaine NJ, Zabaleta J, Mohan M, Winsauer P, Vande Stouwe C (2011a) Cannabinoid neuroimmune modulation of SIV disease. J Neuroimmune Pharmacol 6:516–527PubMedCentralPubMedCrossRefGoogle Scholar
  6. Molina PE, Winsauer P, Zhang P, Walker E, Birke L, Amedee A, Stouwe CV, Troxclair D, McGoey R, Varner K, Byerley L, LaMotte L (2011b) Cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res Hum Retrovir 27:585–592PubMedCentralPubMedCrossRefGoogle Scholar
  7. Molina PE, Amedee AM, Lecapitaine NJ, Zabaleta J, Mohan M, Winsauer P, Vande Stouwe C, McGoey R, Auten MW, Lamotte L, Chandra LC, Birke L (2014) Modulation of Gut-Specific Mechanisms by Chronic Delta9-THC Administration in Male Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Systems Biology Analysis. AIDS Res Hum RetrovirusesGoogle Scholar
  8. Persidsky Y, Ho W, Ramirez SH, Potula R, Abood ME, Unterwald E, Tuma R (2011) HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions. Brain Behav Immun 25(Suppl 1):S61–S70PubMedCentralPubMedCrossRefGoogle Scholar
  9. Ramirez SH, Reichenbach NL, Fan S, Rom S, Merkel SF, Wang X, Ho WZ, Persidsky Y (2013) Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. J Leukoc Biol 93:801–810PubMedCentralPubMedCrossRefGoogle Scholar
  10. Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood–brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004–4016PubMedCentralPubMedCrossRefGoogle Scholar
  11. Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach N, Pacher P, Persidsky Y (2013) Selective activation of cannabinoid receptor 2 (CB2) in leukocytes suppresses their engagement of the brain endothelium and protects the Blood Brain Barrier (BBB). Am J Pathol 183:1548–1558PubMedCentralPubMedCrossRefGoogle Scholar
  12. Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M (1997) A model for monocyte migration through the blood–brain barrier during HIV-1 encephalitis. J Immunol 158:3499–3510PubMedGoogle Scholar
  13. Persidsky Y, Heilman D, Haorah J, Zelivyanskaya M, Persidsky R, Weber GA, Shimokawa H, Kaibuchi K, Ikezu T (2006) Rho-mediated regulation of tight junctions during monocyte migration across the blood–brain barrier in HIV-1 encephalitis (HIVE). Blood 107:4770–4780PubMedCentralPubMedCrossRefGoogle Scholar
  14. Ramirez SH, Heilman D, Morsey B, Potula R, Haorah J, Persidsky Y (2008) Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses Rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. J Immunol 180:1854–1865PubMedCentralPubMedCrossRefGoogle Scholar
  15. Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS et al (1988) Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 167:1428–1441PubMedCrossRefGoogle Scholar
  16. Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Ramirez SH, Persidsky Y (2014) Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood–brain barrier under physiologic and neuroinflammatory conditions. J Cereb Blood Flow MetabGoogle Scholar
  17. Ramirez SH, Fan S, Zhang M, Papugani A, Reichenbach N, Dykstra H, Mercer AJ, Tuma RF, Persidsky Y (2010a) Inhibition of Glycogen Synthase Kinase 3{beta} (GSK3{beta}) decreases inflammatory responses in brain endothelial cells. Am J Pathol 176:881–892PubMedCentralPubMedCrossRefGoogle Scholar
  18. Graham SM, Mwilu R, Liles WC (2013) Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection: A systematic review. Virulence 4Google Scholar
  19. Ramirez SH, Fan S, Dykstra H, Reichenbach N, Del Valle L, Potula R, Phipps RP, Maggirwar SB, Persidsky Y (2010b) Dyad of CD40/CD40 ligand fosters neuroinflammation at the blood–brain barrier and is regulated via JNK signaling: implications for HIV-1 encephalitis. J Neurosci 30:9454–9464PubMedCentralPubMedCrossRefGoogle Scholar
  20. Sui Z, Sniderhan LF, Schifitto G, Phipps RP, Gelbard HA, Dewhurst S, Maggirwar SB (2007) Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia. J Immunol 178:3226–3236PubMedCrossRefGoogle Scholar
  21. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T (2008) Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol 172:521–533PubMedCentralPubMedCrossRefGoogle Scholar
  22. Kaul M, Lipton SA (2006) Mechanisms of neuroimmunity and neurodegeneration associated with HIV-1 infection and AIDS. J Neuroimmune Pharmacol 1:138–151PubMedCrossRefGoogle Scholar
  23. (2014) High time for advancing marijuana research. Nat Neurosci 17: 481Google Scholar
  24. Letendre SL, Zheng JC, Kaul M, Yiannoutsos CT, Ellis RJ, Taylor MJ, Marquie-Beck J, Navia B (2011) Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals. J Neurovirol 17:63–69PubMedCentralPubMedCrossRefGoogle Scholar
  25. Spudich SS (2014) CROI 2014: neurologic complications of HIV infection. Top Antivir Med 22:594–601PubMedGoogle Scholar
  26. Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69PubMedCrossRefGoogle Scholar
  27. Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41:161–168PubMedCrossRefGoogle Scholar
  28. Kraft-Terry SD, Stothert AR, Buch S, Gendelman HE (2010) HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis 37:542–548PubMedCentralPubMedCrossRefGoogle Scholar
  29. Klegeris A, Bissonnette CJ, McGeer PL (2003) Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol 139:775–786PubMedCentralPubMedCrossRefGoogle Scholar
  30. Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79PubMedCrossRefGoogle Scholar
  31. Molina-Holgado F, Molina-Holgado E, Guaza C (1998) The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler’s murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett 433:139–142PubMedCrossRefGoogle Scholar
  32. Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M, Pintado B, Gutierrez-Adan A, Sanguino E, Bellora N, Manzanares J, Zimmer A, Maldonado R (2008) Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 28:12136–12145PubMedCentralPubMedCrossRefGoogle Scholar
  33. Gorantla S, Makarov E, Roy D, Finke-Dwyer J, Murrin LC, Gendelman HE, Poluektova L (2010) Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. J Neuroimmune Pharmacol 5:456–468PubMedCentralPubMedCrossRefGoogle Scholar
  34. Suh J, Sinclair E, Peterson J, Lee E, Kyriakides TC, Li FY, Hagberg L, Fuchs D, Price RW, Gisslen M, Spudich S (2014) Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection. J Neuroinflammation 11:199PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yuri Persidsky
    • 1
    • 2
    Email author
  • Shongshan Fan
    • 1
    • 2
  • Holly Dykstra
    • 1
    • 2
  • Nancy L. Reichenbach
    • 1
    • 2
  • Slava Rom
    • 1
    • 2
  • Servio H. Ramirez
    • 1
    • 2
    • 3
  1. 1.Department of Pathology and Laboratory MedicineTemple University School of MedicinePhiladelphiaUSA
  2. 2.Center for Substance Abuse ResearchTemple University School of MedicinePhiladelphiaUSA
  3. 3.Shriners Hospitals Pediatric Research CenterTemple University School of MedicinePhiladelphiaUSA

Personalised recommendations