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Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade.
Glia ( IF 5.4 ) Pub Date : 2019-05-14 , DOI: 10.1002/glia.23639 Lixia Du 1 , Xueming Hu 1 , Wei Yang 1 , Hanikezi Yasheng 1 , Shenbin Liu 1 , Wenwen Zhang 1 , Yang Zhou 1 , Wenqiang Cui 1 , Jianyu Zhu 1 , Zheng Qiao 1 , Qiliang Maoying 1 , Yuxia Chu 1 , Hong Zhou 2 , Yanqing Wang 1 , Wenli Mi 1
Glia ( IF 5.4 ) Pub Date : 2019-05-14 , DOI: 10.1002/glia.23639 Lixia Du 1 , Xueming Hu 1 , Wei Yang 1 , Hanikezi Yasheng 1 , Shenbin Liu 1 , Wenwen Zhang 1 , Yang Zhou 1 , Wenqiang Cui 1 , Jianyu Zhu 1 , Zheng Qiao 1 , Qiliang Maoying 1 , Yuxia Chu 1 , Hong Zhou 2 , Yanqing Wang 1 , Wenli Mi 1
Affiliation
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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.
中文翻译：
脊髓IL-33 / ST2信号通过星形细胞JAK2-STAT3级联介导小鼠的慢性瘙痒。
白介素33（IL-33）及其受体ST2促进了脊髓神经胶质的活化和慢性疼痛。最近的一项研究表明，外周血IL-33在常春藤引起的慢性瘙痒的发病机理中起着关键作用。但是，脊髓中IL-33 / ST2信号如何潜在地介导慢性瘙痒仍然难以捉摸。在这里，我们确定St2-/-大大减少了2,4-二硝基氟苯（DNFB）诱导的过敏性接触性皮炎（ACD）以及丙酮和乙醚的by抓行为，然后水诱导了小鼠的皮肤干燥。鞘内注射中和性抗ST2或抗IL-33抗体可显着降低DNFB诱导的ACD小鼠的抓挠反应。脊髓IL-33和ST2的表达在ACD小鼠中显着增加，这可以通过mRNA和蛋白质水平的提高来证明。免疫荧光和原位杂交表明，脊髓IL-33的表达增加在少突胶质细胞和星形胶质细胞中占主导，而ST2主要在星形胶质细胞中表达。进一步的研究表明，在ACD小鼠中，St2-/-显着减弱了星形胶质细胞的激活以及信号转导子和转录激活子3（STAT3）磷酸化的增强。鞘内注射Janus Kinase 2 Inhibitor AG490可显着缓解ACD小鼠的抓挠行为。rIL-33预处理加剧了胃泌素释放肽（GRP）引起的抓挠行为。胃泌素释放肽受体（GRPR）的这种增加的表达被St2-/-消除。Tnf-α的上调被St2-/-抑制。我们的结果表明，脊髓IL-33 / ST2信号通路通过星形细胞JAK2-STAT3级联激活促进慢性瘙痒，促进TNF-α释放以调节GRP / GRPR信号传导相关的瘙痒反应。因此，这些发现为治疗慢性瘙痒症提供了潜在的治疗选择。
更新日期：2019-05-14
中文翻译：
脊髓IL-33 / ST2信号通过星形细胞JAK2-STAT3级联介导小鼠的慢性瘙痒。
白介素33（IL-33）及其受体ST2促进了脊髓神经胶质的活化和慢性疼痛。最近的一项研究表明，外周血IL-33在常春藤引起的慢性瘙痒的发病机理中起着关键作用。但是，脊髓中IL-33 / ST2信号如何潜在地介导慢性瘙痒仍然难以捉摸。在这里，我们确定St2-/-大大减少了2,4-二硝基氟苯（DNFB）诱导的过敏性接触性皮炎（ACD）以及丙酮和乙醚的by抓行为，然后水诱导了小鼠的皮肤干燥。鞘内注射中和性抗ST2或抗IL-33抗体可显着降低DNFB诱导的ACD小鼠的抓挠反应。脊髓IL-33和ST2的表达在ACD小鼠中显着增加，这可以通过mRNA和蛋白质水平的提高来证明。免疫荧光和原位杂交表明，脊髓IL-33的表达增加在少突胶质细胞和星形胶质细胞中占主导，而ST2主要在星形胶质细胞中表达。进一步的研究表明，在ACD小鼠中，St2-/-显着减弱了星形胶质细胞的激活以及信号转导子和转录激活子3（STAT3）磷酸化的增强。鞘内注射Janus Kinase 2 Inhibitor AG490可显着缓解ACD小鼠的抓挠行为。rIL-33预处理加剧了胃泌素释放肽（GRP）引起的抓挠行为。胃泌素释放肽受体（GRPR）的这种增加的表达被St2-/-消除。Tnf-α的上调被St2-/-抑制。我们的结果表明，脊髓IL-33 / ST2信号通路通过星形细胞JAK2-STAT3级联激活促进慢性瘙痒，促进TNF-α释放以调节GRP / GRPR信号传导相关的瘙痒反应。因此，这些发现为治疗慢性瘙痒症提供了潜在的治疗选择。
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