Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system

Allan, Debbie; Fairlie‐Clarke, Karen; Elliott, Carl; Schuh, Cornelia; Barnett, Susan C.; Lassmann, Hans; Linnington, Christopher; Jiang, Hui-Rong

doi:10.1186/s40478-016-0344-1

Cited by 59 publications

(67 citation statements)

References 41 publications

(56 reference statements)

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“…The findings in this study show that the addition of IL‐33 proteins can increase the IL‐33 expression in OPCs and promote the production of O4 + ‐OLGs and MBP + ‐OLGs in the culture (Natarajan et al ). In contrast, findings from prior studies have indicated that prolonged treatment of myelinating spinal cord co‐cultures with recombinant IL‐33 proteins significantly reduced the number of MBP + ‐axons (Allan et al ). It seems that exogenous IL‐33 is beneficial to OLG differentiation from OPCs, but is detrimental to the myelinogenesis in myelinating OLGs.…”

Section: Discussionmentioning

confidence: 80%

“…Despite that these findings implicate the effect of IL‐33 on OPCs and myelinating OLGs through interaction with its receptor ST2, evidence showing the involvement of ST2 in OPCs and OLG differentiation is indeed poor. Numerous studies have also indicated that the effects of OLG‐derived IL‐33 on the functions of microglia and astrocytes manifest through the action of its ST‐2 receptor on microglia and astrocytes (Allan et al ; Zarpelon et al ; Yang et al ; Du et al ). Yet, the pathway that mediates the release of IL‐33 from the nuclear location of OLGs to the extracellular space has not yet been uncovered.…”

Section: Discussionmentioning

confidence: 99%

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Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression

Sung

Chen

Huang

et al. 2019

Journal of Neurochemistry

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Interleukin‐33 (IL‐33), a member of the IL1 family, has been found to be expressed in oligodendrocytes (OLGs) and released as an alarmin from injured OLGs to work on other glial cell‐types in the central nervous system. However, its functional role in OLGs remains unclear. Herein, we present that IL‐33 was mainly expressed in the nucleus of CC1+‐oligodendrocytes (OLGs) in mouse and rat corpus callosum, as well as NG2+‐oligodendrocyte precursor cells (OPCs). The in vitro study indicated that the amount of IL‐33 expressing in OPCs was higher when compared to that detected in OLGs. Results from the experiments using lentivirus‐mediated shRNA delivery against IL‐33 expression (IL33‐KD) in OPCs showed that IL33‐KD reduced the differentiation of OLGs into mature OLGs along with the down‐regulation of OLG differentiation‐related genes and mature OLG marker proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Alternatively, we observed reduced differentiation of OLGs that were prepared from the brains of IL‐33 gene knockout (IL33‐KO) mice with anxiolytic‐like behavior. Observations were correlated with the results showing lower levels of MBP and PLP in IL33‐KO cultures than those detected in the control cultures prepared from wildtype (WT) mice. Transmission Electron Microscopy (TEM) analysis revealed that the myelin structures in the corpus callosum of the IL33‐KO mice were impaired compared to those observed in the WT mice. Overall, this study provides important evidence that declined expression of IL‐33 in OPCs suppresses the maturation of OLGs. Moreover, gene deficiency of IL‐33 can disrupt OLG maturation and interfere with myelin compaction. Cover Image for this issue: doi:

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression

Sung

Chen

Huang

et al. 2019

Journal of Neurochemistry

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“…Our previous results showed that astrocytes and neurons were the primary sources of ST2 in the spinal cord of the SNI model (Liu et al, ) or cancer pain model (Zhao, Zhang, et al, ). Furthermore, ST2 was found to be predominantly expressed in oligodendrocytes in MS patient brains (Allan et al, ). Most recently, using flow cytometry, cerebral ST2 was shown to be abundantly expressed in the microglia and astrocytes, but not in oligodendrocytes (Yang et al, ), while another study demonstrated most of its expression in microglia of the spinal cord (Vainchtein et al, ).…”

Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

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“…Of note, IL17D, as all the members of the IL17 family, is also a potent inducer of TGFB secretion in many cell types [66,67]. Interestingly also, the astrocytic expression of IL-33 was recently demonstrated in MS plaques and IL33 was shown to inhibit the de novo myelination of rat axons in vitro [68]. However, other works reported that IL-33 promotes remyelination [69] and exerts potent anti-inflammatory and neuroprotective functions [70].…”

Section: Discussionmentioning

confidence: 97%

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

Nataf¹,

Barritault²,

Pays³

2017

Preprint

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Abstract:We previously reported that in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis and low-grade inflammation. However, transcriptomic analyses comparing periplaques to adjacent normal-appearing white matter (NAWM) areas did not allow providing a comprehensive view of molecular events in astrocytes vs oligodendrocytes. Here, we re-assessed our transcriptomic data with the aim of identifying functionally-relevant co-expression networks that would reflect astrocyte vs oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related gene module comprising GFAP, the hub gene CX43/GJA1 and a set of transcripts forming a TGFB/SMAD1/SMAD2 genomic signature. Partial demyelination was characterized by a co-expression network which, besides myelin genes, comprised a highly significant number of translation/elongation-related genes. Interestingly, the main oligodendrocyte-related hub we identified was NDRG1, a gene previously shown to be specifically silenced in the NAWM of MS patients. This result indicated that NDRG1 down-regulation could be an important event in the process of periplaque partial demyelination. To establish a putative link between NDRG1 down-regulation and a cytokine/chemokine signature, we then sought to identify cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach we found 5 candidate immune-related genes whose up-regulation associated with NDRG1 down-regulation: TGFB1, PDGFC, . From these results we propose that in the spinal cord of MS patients with progressive forms of the disease, TGFB1 may Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system

Cited by 59 publications

References 41 publications

Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression

Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

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