Molecular Immunology 45 (2008) 3767–3774 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Role of complement anaphylatoxin receptors (C3aR, C5aR) in the development of the rat cerebellum Magalie Bénard a,b,c,∗ , Emilie Raoult a,b , David Vaudry a,b,c , Jérome Leprince a,b,c , Anthony Falluel-Morel a,b , Bruno J. Gonzalez a,b,1 , Ludovic Galas b,c , Hubert Vaudry a,b,c , Marc Fontaine a,b a Inserm U413, Laboratory of Cellular and Molecular Neuroendocrinology, 76821 Mont-Saint-Aignan, France b European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821 Mont-Saint-Aignan, France c Platform for Cell Imaging of Normandy RIO/IBiSA, Mont-Saint-Aignan, France article info Article history: Received 8 April 2008 Received in revised form 26 May 2008 Accepted 28 May 2008 Available online 16 July 2008 Keywords: Complement Anaphylatoxin Development Cerebellum abstract There is now strong evidence for non-immune or inflammatory functions of complement, notably in the central nervous system. In particular, it has been recently reported that the anaphylatoxin receptors C3aR and C5aR are transiently expressed in the cerebellar cortex of newborn rat, suggesting that anaphylatoxins are involved in the histogenesis of the cerebellum. In the present study, we have investigated the effects of C3aR and C5aR agonists and antagonists on the development of the cerebellum of 11–12-day-old rats in vivo and in vitro. Sub-dural injection of C3aR and C5aR agonists at the surface of the cerebellum transiently modified the thickness of the cortical layers. The C5aR agonist provoked an enlargement of the external granule cell layer (EGL) that was due to increased proliferation of immature granule neurons. Conversely, the C3aR agonist decreased the thickness of the EGL and increased the thickness of the internal granule cell layer (IGL), suggesting that C3a accelerates the migration process of granule cells from the EGL to the IGL. Video-microscopy examination of cultured granule neurons confirmed the role of C3aR in cell motility. These results provide clear evidence for the involvement of anaphylatoxin receptors in the histogenesis of the cerebellar cortex. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction The complement system is traditionally known as an effec- tor arm of humoral immunity activated in response to infection or injury. Pathogens are eliminated either directly by lysis through the formation of the membrane attack complex or indirectly by activating phagocytic cells of the innate immune system (macrophages and neutrophils) and by eliciting a strong antibody response by activating B lymphocytes. Complement activation provoked by an injury induces a strong inflamma- tory reaction by recruiting and activating inflammatory cells. Most of these complement-mediated effects are triggered by complement fragments, generated during its activation and inac- tivation, which bind to a large variety of specific receptors ∗ Corresponding author at: Inserm U413, Laboratory of Cellular and Molecular Neuroendocrinology, 76821 Mont-Saint-Aignan, France. Tel.: +33 235 14 6760; fax: +33 235 14 6946. E-mail address: magalie.benard@univ-rouen.fr (M. Bénard). 1 Present address: Inserm AVENIR, IFRMP 23, University of Rouen, 76183 Rouen, France. present on cells of the myeloid and lymphoid lineages (Volanakis, 1998). Complement is mainly produced by the liver and present in blood. However, many cell types have been described as local com- plement sources in different organs suggesting non-inflammatory or non-immune roles for these tissue complement pools (Mastellos and Lambris, 2002). For instance, the third component of comple- ment, C3, has been shown to participate to bone resorption (Sato et al., 1993) and to the reproduction process to facilitate the fusion between spermatozoid and oocyte (Ember et al., 1998). Among the different fragments liberated during activation of the complement cascade, C3a and C5a anaphylatoxins are potent pro-inflammatory mediators. C3a and C5a exert their biological effects through specific receptors, termed respectively C3aR and C5aR, that are mainly expressed by cells of the myeloid lineage (Liszewski et al., 2005). The recent evidence of C3aR and/or C5aR expression by cells of non-myeloid origin suggests the possible involvement of these complement components during develop- ment and tissue repair (Mastellos and Lambris, 2002). In support of this hypothesis, in an urodele model of tissue regeneration, C3 and C5 expression correlates with regeneration of lens and limb (Kimura et al., 2003) and, in rodents, C3a and C5a are necessary for 0161-5890/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2008.05.027