Dual role of inflammation in CNS disease

Hohlfeld, Reinhard; Kerschensteiner, Martin; Meinl, Edgar

doi:10.1212/01.wnl.0000275234.43506.9b

Cited by 99 publications

(71 citation statements)

References 45 publications

(56 reference statements)

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“…Given the intimate and complex relationship between inflammation and remyelination (Hohlfeld et al, 2007;Rodriguez, 2007;Sharief, 1998), it has been suggested that modulation of the local inflammatory milieu might prove to be the most promising therapeutic approach to support remyelination in MS lesions (Franklin and Ffrench-Constant, 2008). Nonetheless, any enterprise to devise therapeutic interventions that would aim at establishing or ameliorating the remyelination-supportive cellular environment in the CNS of patients with MS has been greatly hindered by the lack of knowledge regarding the exact nature of this cellular environment.…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

314

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

314

270

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“…This dual role of TNF-α may underlie the poor outcome observed with inhibition of TNF-α signaling in MS clinical trials [31,32]. TNF signaling is an example of the difficulty of predicting effects of growth factors and cytokines associated with inflammation, which can positively and negatively impact remyelination [33,34]. A further example is that induction of localized inflammation promoted remyelination of transplanted cells in the context of chronic demyelination [35].…”

Section: Stimulating Proliferation To Counter Op Depletion In Chronicmentioning

confidence: 99%

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

Armstrong

2007

Future Neurol.

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Remyelination facilitates recovery of saltatory conduction along demyelinated axons and may help prevent axon damage in patients with demyelinating diseases, such as multiple sclerosis. The extent of remyelination in multiple sclerosis lesions varies dramatically, indicating a capacity for repair that is not fulfilled in lesions with poor remyelination. In experimental models of demyelinating disease, remyelination is limited by chronic disease that depletes the oligodendrocyte progenitor (OP) population, inhibits OP differentiation into remyelinating oligodendrocytes and/or perturbs cell survival in the lesion environment. Manipulating the activity of growth factor signaling pathways significantly improves the ability of endogenous OP cells to accomplish extensive remyelination. Specifically, growth factors have been identified that can regulate OP proliferation, differentiation and survival in demyelinated lesions. Therefore, growth factors may be key signals for strategies to improve conditions with poor remyelination. Keywords cuprizone; demyelinating disease; FGF; multiple sclerosis; myelin; oligodendrocyte; PDGF; progenitors; remyelination Transition to in vivo analysis during remyelinationAnalysis of growth factors to promote repair in demyelinating diseases has undergone an important transition to in vivo studies and in doing so has revealed much more than the expected results. Characterization of the bipotential oligodendrocyte-type 2 astrocyte or oligodendrocyte progenitor (OP) cell, and the regulation of cell fate by serum components [1] opened the door for in vitro analysis of growth factor responses in the oligodendrocyte lineage. Numerous subsequent in vitro studies identified specific growth factors capable of regulating differentiation, proliferation, migration and survival at specific stages within this lineage. In vitro studies continue to offer distinct advantages for isolating molecular and cellular mechanisms of action and for characterizing the potential of defined growth factors to induce a specific cellular response. In this context, several cytokines and chemokines have been identified as having direct effects on oligodendrocyte lineage cells that are similar to growth factor actions and so they will be discussed together under the rubric of growth factors. This review will focus on recent in vivo remyelination studies designed to test potential growth factor responses identified in vitro. These in vivo studies demonstrate important effects of growth factors in the context of demyelinating disease models in rodents. However, not all growth factor analyses have resulted in the predicted responses. Importantly, several studies have demonstrated a remarkable capacity of endogenous cells to repair the adult CNS, even following chronic demyelination, using modulation of growth factor signaling to better support oligodendrocyte replacement and myelin formation.

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“…Recent literature data show the presence of intense cross-talk between the nervous and the immune system [13,18,30]. The elements of both systems express and secrete a range of cytokines (for the immune system) and neurotrophic factors (for the CNS) that control growth as well as cell differentiation.…”

Section: Resultsmentioning

confidence: 99%