MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47

Junker, Andreas; Krumbholz, Markus; Eisele, Sylvia; Mohan, Hema; Augstein, Florian; Bittner, Robert A.; Lassmann, Hans; Wekerle, Hartmut; Hohlfeld, Reinhard; Meinl, Edgar

doi:10.1093/brain/awp300

Cited by 515 publications

(589 citation statements)

References 57 publications

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“…These cells differentiate and become mature OLs sequentially expressing myelin proteins such as proteolipid protein (PLP), myelin basic protein (MBP), and 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase. These findings prove that remyelination mechanisms are tightly regulated and involve a wide range of molecules, including cytokines (Mason et al 2001) and chemokines (Patel et al 2010), transcription factors (Qi et al 2001), growth factors (Aguirre et al 2007;Murtie et al 2005), micro-RNA (Junker et al 2009), and different signaling pathways (John et al 2002).…”

Section: Underlying Mechanisms In Demyelination/ Remyelination Processesmentioning

confidence: 83%

Nutritional factors and aging in demyelinating diseases

Adamo

2013

Genes Nutr

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Demyelination is a pathological process characterized by the loss of myelin around axons. In the central nervous system, oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Remyelination is a regenerative process by which myelin sheaths are restored to demyelinated axons, resolving functional deficits. This process is often deficient in demyelinating diseases such as multiple sclerosis (MS), and the reasons for the failure of repair mechanisms remain unclear. The characterization of these mechanisms and the factors involved in the proliferation, recruitment, and differentiation of oligodendroglial progenitor cells is key in designing strategies to improve remyelination in demyelinating disorders. First, a very dynamic combination of different molecules such as growth factors, cytokines, chemokines, and different signaling pathways is tightly regulated during the remyelination process. Second, factors unrelated to this pathology, i.e., age and genetic background, may impact disease progression either positively or negatively, and in particular, age-related remyelination failure has been proven to involve oligodendroglial cells aging and their intrinsic capacities among other factors. Third, nutrients may either help or hinder disease progression. Experimental evidence supports the anti-inflammatory role of omega-6 and omega-3 polyunsaturated fatty acids through the competitive inhibition of arachidonic acid, whose metabolites participate in inflammation, and the reduction in T cell proliferation. In turn, vitamin D intake and synthesis have been associated with lower MS incidence levels, while vitamin D-gene interactions might be involved in the pathogenesis of MS. Finally, dietary polyphenols have been reported to mitigate demyelination by modulating the immune response.

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Section: Underlying Mechanisms In Demyelination/ Remyelination Processesmentioning

confidence: 83%

Nutritional factors and aging in demyelinating diseases

Adamo

2013

Genes Nutr

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“…In the brains of MS patients, microRNA expression is significantly altered and has been suggested to significantly influence inflammation and repair capacity 35, 36. In astrocytes, both miR‐155 and miR‐146a are significantly upregulated in active MS lesions; laser‐captured astrocytes from MS lesions express miR‐155 in situ 35.…”

Section: Discussionmentioning

confidence: 99%

“…In astrocytes, both miR‐155 and miR‐146a are significantly upregulated in active MS lesions; laser‐captured astrocytes from MS lesions express miR‐155 in situ 35. Furthermore, activation of astrocytes with various proinflammatory stimuli upregulates the expression of miR‐146a and miR‐155 in vitro 35, 37. The increase in miR‐155 expression by IL‐1 β was confirmed in our study, however, to further elucidate on the mechanism of action for DMF, we demonstrated that fumarates reduced miR‐155 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the validated miR‐155 target SOCS138 is a potent regulator of astrocyte cytokine/chemokine secretion,39 suggesting that a miR‐155/SOCS1 axis could mediate the anti‐inflammatory effects of DMF. miR‐146a is an inflammation resolving microRNA whose expression is upregulated in CNS lesions and peripheral immune cells of MS patients 35, 36. As such, the reduced expression of miR‐146a in fumarate‐treated astrocytes suggests an MS‐relevant resolution of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Galloway

Williams

Moore

2017

Ann Clin Transl Neurol

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ObjectiveDimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed.MethodsPrimary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL‐1β for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.ResultsIn both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL‐6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs ‐146a and ‐155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells.InterpretationThese results suggest that DMF, and to a lesser extent MMF, mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.

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“…It has been demonstrated that Ahr plays a prominent role in EAE pathogenesis, and the activation of Ahr by TCDD ameliorates disease symptoms [5]. Recently, it has been revealed that several miRNAs are associated with the development of MS [28,29] and targeting specific miRNAs showed therapeutic potential in EAE [11][12][13]. However, the interaction between Ahr and miRNAs in EAE is yet unexplored.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Hanieh

Abdullah

2013

Eur J Immunol

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MicroRNAs (miRNAs) are a small group of RNAs that are emerging as a new avenue by which autoimmune diseases may be modulated. Accumulating evidence shows that miRNAs are involved in the pathogenesis of MS; however, the interaction of miRNAs with environmentally responsive transcription factors that play prominent roles in MS is unexplored. The activation of aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alleviates inflammation in experimental autoimmune encephalomyelitis (EAE), the best available model of MS. Therefore, we predicted that TCDD could attenuate EAE by inducing miRNA(s) targeting inflammatory mediators. Here, we show that TCDD induces cholinergic anti-inflammation in EAE mice by upregulating acetylcholinesterasetargeting miR-132. The expression of miR-132 was downregulated in CD4 + cells and associated with EAE severity, while TCDD treatment attenuated EAE by inducing the miR-132/acetylcholinesterase module. Silencing miR-132 in vivo abolished TCDDinduced cholinergic anti-inflammation and aggravated EAE. Overexpression of miR-132 in encephalitogenic CD4 + cells decreased IL-17 and IFN-γ and suppressed T-cell proliferation. In conclusion, our findings identify a new miRNA-based mechanism through which miR-132 mediates TCDD-induced EAE attenuation, suggesting that miR-132 could be a promising therapeutic target for anti-inflammatory treatment of MS.Keywords: Ahr r Cholinergic anti-inflammation r EAE · MicroRNA r miR-132 r TCDD Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor activated by a long list of exogenous ligands including 2,3,7, [1] and 3-methylcholanthrene [2]. Ahr has been shown to mediate the mechanisms that underlie environmental and immunotoxicity [3]. Therefore, Ahr represents a fascinating link between the environment and the immune system. Previously, we and others have Correspondence: Dr. Hanieh Hamza e-mail: hhanieh@kfu.edu.sa demonstrated that Ahr is implicated in the differentiation of Th17/Treg cells [4][5][6], development of autoimmunity [7], and secretion of proinflammatory cytokines [8,9]. Importantly, activation of Ahr has shown a therapeutic potential for autoimmune inflammation. For example, TCDD mitigates CNS inflammation in experimental autoimmune encephalomyelitis (EAE) [5], an established animal model of MS. However, the toxicity of TCDD prohibits its clinical application, and therefore, mechanistic explanation of TCDD-attenuated inflammation may open intriguing possibilities for applicable treatment of MS in human.The microRNAs (miRNAs) are small endogenous noncoding RNAs of ∼22 nt that post-transcriptionally regulate gene expression. These molecules are implicated in different aspects of C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Hanieh Hamza and Alzahrani AbdullahEur. J. Immunol. 2013Immunol. . 43: 2771Immunol. -2782 inflammation. For instance, miR-155, miR-146a, a...

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MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47

Cited by 515 publications

References 57 publications

Nutritional factors and aging in demyelinating diseases

Nutritional factors and aging in demyelinating diseases

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

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