title: MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47.
abstract: We established microRNA profiles from active and inactive multiple sclerosis lesions. Using laser capture microdissection from multiple sclerosis lesions to pool single cells and in vitro cultures, we assigned differentially expressed microRNA to specific cell types. Astrocytes contained all 10 microRNA that were most strongly upregulated in active multiple sclerosis lesions, including microRNA-155, which is known to modulate immune responses in different ways but so far had not been assigned to central nervous system resident cells. MicroRNA-155 was expressed in human astrocytes in situ, and further induced with cytokines in human astrocytes in vitro. This was confirmed with astrocyte cultures from microRNA-155-|-lacZ mice. We matched microRNA upregulated in phagocytically active multiple sclerosis lesions with downregulated protein coding transcripts. This converged on CD47, which functions as a 'don't eat me' signal inhibiting macrophage activity. Three microRNA upregulated in active multiple sclerosis lesions (microRNA-34a, microRNA-155 and microRNA-326) targeted the 3'-untranslated region of CD47 in reporter assays, with microRNA-155 even at two distinct sites. Our findings suggest that microRNA dysregulated in multiple sclerosis lesions reduce CD47 in brain resident cells, releasing macrophages from inhibitory control, thereby promoting phagocytosis of myelin. This mechanism may have broad implications for microRNA-regulated macrophage activation in inflammatory diseases.
authors: Institute for Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany.
authors: Andreas
authors: A
authors: Junker
authors: Markus
authors: M
authors: Krumbholz
authors: Sylvia
authors: S
authors: Eisele
authors: Hema
authors: H
authors: Mohan
authors: Florian
authors: F
authors: Augstein
authors: Robert
authors: R
authors: Bittner
authors: Hans
authors: H
authors: Lassmann
authors: Hartmut
authors: H
authors: Wekerle
authors: Reinhard
authors: R
authors: Hohlfeld
authors: Edgar
authors: E
authors: Meinl
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051928:CD47 Antigen / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D042282:Microdissection; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D016133:Polymerase Chain Reaction
chemical_list: D051928:CD47 Antigen; D035683:MicroRNAs