Semaphorin 7A as a Potential Therapeutic Target for Multiple Sclerosis
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Semaphorin 7A (sema7A) is classified as an immune semaphorin with dual functions in the immune system and in the central nervous system (CNS). These molecules are of interest due to their potential role in multiple sclerosis (MS), which is a chronic demyelinating and neurodegenerative disease of autoimmune origin. In this study, we elucidated the role of sema7A in neuroinflammation using both in vitro and in vivo experimental models. In an in vitro model of neuroinflammation, using cerebellar organotypic slice cultures, we observed that challenge with lipopolysaccharide (LPS) endotoxin did not affect demyelination or cell death in sema7A-deficient cultures compared to wild-type cultures. Moreover, the in vivo outcome of experimental autoimmune encephalomyelitis (EAE) in sema7A-deficient mice was altered in an antigen- and adjuvant-dose-dependent manner, while no differences were observed in the wild-type counterparts. Altogether, these results indicate that sema7A is involved in peripheral immunity and CNS inflammation in MS pathogenesis. Indeed, these data suggest that sema7A might be a potential therapeutic target to treat MS and autoimmune conditions.
KeywordsSemaphorin 7A Experimental autoimmune encephalomyelitis Multiple sclerosis Neuroinflammation Neurodegeneration
We thank Prof. A. Kolodkin for kindly providing the sema7A-KO mice, D. Johnson for helping with the transfer of the animals and assistance with genotyping and Prof. R. J Pasterkamp for providing the sema7A and Plexin-C1 cDNA probes. This project was supported by the Fondo de Investigación Sanitaria (FIS; Instituto de Salud Carlos III, Ministry of Economy and Competitiveness in Spain; PI12/02144, granted to CE) and “Red Española de Esclerosis Múltiple (REEM)” (RD12/0032) which is sponsored by the FIS, and the “Ajuts per donar Suport als Grups de Recerca de Catalunya” (2014 SGR 1082) which is sponsored by the “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR; Generalitat de Catalunya). It was also supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (BFU2012-32617 and BFU2015-67777-R), the Spanish prion network (Prionet Spain, AGL2015-71764-REDT), CIBERNED (PI2014/02-4 and PRY-14-114), La Caixa Obra Social Foundation (P1-L14) and La Marató de TV3 (20143410) granted to JADR. AG-F was supported by the PFIS programme (FI10/00456), HE was supported by the “Sara Borrell” programme (CD09/00363) and CE is supported by the “Miguel Servet” programme (CP13/00028), all of which are under the FIS. VG is supported by a Juan de la Cierva post-doctoral fellowship of MINECO (JCI-2012-14356).
Compliance with Ethical Standards
Research Involving Animals
All experiments were performed in strict accordance with EU (Directive 2010/63/UE) and Spanish regulations (Real Decreto 53/2013; Generalitat de Catalunya Decret 214/97). The Ethics Committee on Animal Experimentation of the Vall d’Hebron Research Institute and the University of Barcelona approved all procedures described in this study (protocol number: 39/09 CEEA–DAAM 5612, and 141/15 and 329/14 respectively).
Disclosure of Potential Conflict of Interest
AGF, HE, CC, MC, VG, LCB, JADR, CE declare no financial conflict of interest.
XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
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