Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation.
In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen-directed T lymphocyte-mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS-specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35-55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX)-positive immature neurons when compared with controls immunized with CNS-irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro-neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, β-catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen-specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS.
Department of Neurology, Charité University Medicine, CCM, Berlin, Germany.
Petra
P
Huehnchen
Timour
T
Prozorovski
Philipp
P
Klaissle
Anne
A
Lesemann
Jens
J
Ingwersen
Susanne A
SA
Wolf
Andreas
A
Kupsch
Orhan
O
Aktas
Barbara
B
Steiner
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002452:Cell Count; D000089662:Doublecortin Protein; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000276:immunology* / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D009186:Myelin Sheath / Q000276:immunology*; D055495:Neurogenesis / Q000276:immunology*; D009474:Neurons / Q000276:immunology; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction