The chemokine receptor CCR5 in the central nervous system Silvia Sorce a , Renier Myburgh a,b , Karl-Heinz Krause a,c, * a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1211 Geneva-4, Switzerland b Department of Immunology, Faculty of Health Sciences, University of Pretoria, Prinshof Campus, 0002 Pretoria, South Africa c Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Switzerland Contents 1. Introduction ..................................................................................................... 297 1.1. The CCR5 gene: structure, regulation and species similarities ........................................................ 298 1.2. CCR5 variants in humans: focus on the CCR5D32 deletion .......................................................... 298 1.3. CCR5-deficient mice ......................................................................................... 299 1.4. Cell biology and function of CCR5 in the immune system ........................................................... 299 1.5. CCR5 antagonists for HIV therapy .............................................................................. 299 2. The CCR5 receptor in the brain: distribution and functions ............................................................... 301 2.1. Distribution ................................................................................................ 301 2.2. Functions .................................................................................................. 301 2.2.1. Physiological functions ............................................................................... 301 2.2.2. Pathological functions ................................................................................ 303 3. Conclusions and perspectives ....................................................................................... 306 Acknowledgements ............................................................................................... 306 References ...................................................................................................... 306 1. Introduction Chemokines are small proteins (70–90 aminoacids), divided into four different groups according to the position of conserved cysteines (C) in their sequence: CXC or alpha, CC or beta, C or gamma and CXC3 or delta chemokines (Rossi and Zlotnik, 2000). The word ‘‘chemokine’’ is derived from their function as chemotactic cytokines, resulting in activation and migration of leukocytes toward sites of inflammation. This process is mediated Progress in Neurobiology 93 (2011) 297–311 ARTICLE INFO Article history: Received 27 September 2010 Received in revised form 29 November 2010 Accepted 7 December 2010 Available online 14 December 2010 Keywords: Brain Chemokines Neurons Microglia Astrocytes HIV-associated dementia West Nile virus Neuroprotection ABSTRACT The expression and the role of the chemokine receptor CCR5 have been mainly studied in the context of HIV infection. However, this protein is also expressed in the brain, where it can be crucial in determining the outcome in response to different insults. CCR5 expression can be deleterious or protective in controlling the progression of certain infections in the CNS, but it is also emerging that it could play a role in non-infectious diseases. In particular, it appears that, in addition to modulating immune responses, CCR5 can influence neuronal survival. Here, we summarize the present knowledge about the expression of CCR5 in the brain and highlight recent findings suggesting its possible involvement in neuroprotective mechanisms. ß 2011 Published by Elsevier Ltd. Abbreviations: CNS, central nervous system; CC, chemokine receptor 5 (CCR5); CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; MIP-1a, macrophage inflammatory protein 1 alpha; MIP-1b, macrophage inflammatory protein 1 beta; RANTES, regulated on activation T cell expressed and secreted; TBE, tick-borne encephalitis; WNV, West Nile virus. * Corresponding author at: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1211 Geneva-4, Switzerland. Tel.: +41 22 3794131; fax: +41 22 3794130. E-mail address: Karl-Heinz.Krause@unige.ch (K.-H. Krause). Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 0301-0082/$ – see front matter ß 2011 Published by Elsevier Ltd. doi:10.1016/j.pneurobio.2010.12.003