We address the issues of neuronal damage and reactive astrogliosis in murine models of multiple sclerosis, an autoimmune disorder of the central nervous sytem (CNS), in which the myelin sheet and oligodendrocytes have been regarded as major primary targets by the immune system. Recent work addresses the issue of the pathogenic arm of reactive astrocytes which are now recognized as important players in amplifying neuroinflammation, damage of oligodendrocytes and axon loss, and how this astrocytic reactivity can be moderated by drugs. We identified astrocytic CCL2 (Fig. 1) as a target of the anti-neuroinflammatory actions of estrogen during ongoing experimental encephalomyelitis (Nicot 2009; Giraud et al, 2010).
Fig. 1 CCL2-producing astrocytes (in green) with infiltrated CD45+ (red) in the white matter of a mouse model of multiple sclerosis.
Current work further focuses on defining the molecular profile of reactive gliosis in the context of CNS auto-immunity, with defining antibody/lymphocyte autoreactivity that could be involved in multiple sclerosis. This is achieved by using multiple sclerosis samples and murine models of CNS autoimmunity and by analysis mRNA expression of ex vivo cell populations enriched by FACS or by laser capture microdissection (LMD, Fig. 2).
Fig. 2. Immuno-labeled cells are captured by laser microdissection and processed for selective gene transcript profiling using plate arrays (Guillot et al, 2015; Nicot et al, 2017).
Founding : Pays de Loire Region (2011-2015), FRC equipment (2011), Inserm-Transfert (2016), ANR collaborative grant 2017-2020 on CNS drug metabolism.
Selected publications (of 51)
1/ Guillot F, Garcia A, Salou M, Brouard S, Laplaud DA, Nicot AB. Transcript analysis of laser capture microdissected white matter astrocytes and higher phenol sulfotransferase 1A1 expression during autoimmune neuroinflammation. J Neuroinflammation. 2015 Jul 4;12:130.
2/ Louveau A, Nerrière-Daguin V, Vanhove B, Naveilhan P, Neunlist M, Nicot A, Boudin H. Targeting the CD80/CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth. Glia. 2015 Dec;63(12):2298-312. Salou M, Garcia A, Michel L, Gainche-Salmon A, Loussouarn D, Nicol B, Guillot F, Hulin P, Nedellec S, Baron D, Ramstein G, Soulillou JP, Brouard S, Nicot AB, Degauque N, Laplaud DA. Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis. Ann Clin Transl Neurol. 2015 Jun;2(6):609-22. Elkabes S, Nicot AB. Sex steroids and neuroprotection in spinal cord injury: a review of preclinical investigations. Exp Neurol. 2014 Sep;259:28-37.Degauque N, Elong Ngono A, Akl A, Lepetit M, Crochette R, Giral M, Lepourry J,Pallier A, Castagnet S, Dugast E, Guillot-Gueguen C, Jacq-Foucher M, Saulquin X, Cesbron A, Laplaud D, Nicot A, Brouard S, Soulillou JP. Characterization of antigen-specific B cells using nominal antigen-coated flow-beads. PLoS One. 2013 Dec 30;8(12):e84273. Gourdain P, Ballerini C, Nicot AB, Carnaud C. Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system. J Neuroinflammation. 2012 Jan 26;9:25.
3/ Giraud SN, Caron CM, Pham-Dinh D, Kitabgi P, Nicot AB. Estradiol inhibits ongoing autoimmune neuroinflammation and NFkappaB-dependent CCL2 expression in reactive astrocytes. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8416-21.
4/ Le Dréau G, Kular L, Nicot AB, Calmel C, Melik-Parsadaniantz S, Kitabgi P,Laurent M, Martinerie C. NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through beta1 and beta5 integrins. Glia. 2010 Sep;58(12):1510-21.Nicot A. Gender and sex hormones in multiple sclerosis pathology and therapy.Front Biosci. 2009 Jan 1;14:4477-515. Review.
5/ Nicot A, Ratnakar PV, Ron Y, Chen CC, Elkabes S (2003) Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction. Brain 126:398-412.
6/ E DiCicco-Bloom, A Nicot, N Lu, J Suh. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an anti-mitogenic signal for selected neuronal precursors in vivo US Patent App. 10/044,722 (2002); 11/240,737 (2005).