Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease

Journal of Neuroinflammation

Avraham Ben-Nun³  Naoto Kawakami²  Nathali Kaushansky³  Rina Zilkha-Falb¹ 

[1] Present address: Multiple Sclerosis Center, Neurogenomics Laboratory, Sheba Medical Center, Tel-Hashomer, Israel;Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, 81377, Germany;Department of Immunology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel

关键词: Myelin and neuronal repair;    Oligodendrocyte precursor cells;    Neuronal progenitor cells;    CXCL12;    Experimental autoimmune encephalomyelitis (EAE);    Multiple sclerosis;   

Others  :  1235602
DOI  :  10.1186/s12974-015-0468-4

 received in 2015-07-09, accepted in 2015-12-26,  发布年份 2016

【 摘 要 】

Background

Demyelination and axonal degeneration, hallmarks of multiple sclerosis (MS), are associated with the central nervous system (CNS) inflammation facilitated by C-X-C motif chemokine 12 (CXCL12) chemokine. Both in MS and in experimental autoimmune encephalomyelitis (EAE), the deleterious CNS inflammation has been associated with upregulation of CXCL12 expression in the CNS. We investigated the expression dynamics of CXCL12 in the CNS with progression of clinical EAE and following spontaneous recovery, with a focus on CXCL12 expression in the hippocampal neurogenic dentate gyrus (DG) and in the corpus callosum (CC) of spontaneously recovered mice, and its potential role in promoting the endogenous myelin/neuronal repair capacity.

Methods

CNS tissue sections from mice with different clinical EAE phases or following spontaneous recovery and in vitro differentiated adult neural stem cell cultures were analyzed by immunofluorescent staining and confocal imaging for detecting and enumerating neuronal progenitor cells (NPCs) and oligodendrocyte precursor cells (OPCs) and for expression of CXCL12.

Results

Our expression dynamics analysis of CXCL12 in the CNS with EAE progression revealed elevated CXCL12 expression in the DG and CC, which persistently increases following spontaneous recovery even though CNS inflammation has subsided. Correspondingly, the numbers of NPCs and OPCs in the DG and CC, respectively, of EAE-recovered mice increased compared to that of naïve mice (NPCs, p < 0.0001; OPCs, p < 0.00001) or mice with active disease (OPCs, p < 0.0005). Notably, about 30 % of the NPCs and unexpectedly also OPCs (~50 %) express CXCL12, and their numbers in DG and CC, respectively, are higher in EAE-recovered mice compared with naïve mice and also compared with mice with ongoing clinical EAE (CXCL12 ⁺NPCs, p < 0.005; CXCL12 ⁺OPCs, p < 0.0005). Moreover, a significant proportion (>20 %) of the CXCL12 ⁺NPCs and OPCs co-express the CXCL12 receptor, CXCR4, and their numbers significantly increase with recovery from EAE not only relative to naïve mice (p < 0.0002) but also to mice with ongoing EAE (p < 0.004).

Conclusions

These data link CXCL12 expression in the DG and CC of EAE-recovering mice to the promotion of neuro/oligodendrogenesis generating CXCR4 ⁺CXCL12 ⁺neuronal and oligodendrocyte progenitor cells endowed with intrinsic neuro/oligondendroglial differentiation potential. These findings highlight the post-CNS-inflammation role of CXCL12 in augmenting the endogenous myelin/neuronal repair capacity in MS-like disease, likely via CXCL12/CXCR4 autocrine signaling.

【 授权许可】

   
2016 Zilkha-Falb et al.

【 图 表 】

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