Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade
Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade
复制标题
脊髓 IL-33/ST2 信号通过星形胶质细胞 JAK2-STAT3 级联介导小鼠慢性瘙痒
作者：
Du, Lixia;Hu, Xueming;Mi, Wenli
白细胞介素-33（IL-33）及其受体ST 2促进脊髓胶质细胞活化和慢性疼痛。最近的研究表明，外周IL-33在毒葛引起的慢性瘙痒的发病机制中起着关键作用。然而，脊髓中的IL-33/ST 2信号传导如何潜在地介导慢性瘙痒仍然是难以捉摸的。在此，我们确定St 2（-/-）显著降低了2，4-二硝基氟苯（DNFB）诱导的过敏性接触性皮炎（ACD）以及丙酮和乙醚随后水诱导的小鼠皮肤干燥中的抓挠行为。鞘内注射中和性抗ST 2或抗IL-33抗体可显著降低DNFB诱导的ACD小鼠的抓挠反应。脊髓IL-33和ST 2的表达在ACD小鼠中显著增加，如通过增加的mRNA和蛋白质水平所证明的。免疫荧光和原位杂交结果表明，脊髓中IL-33的表达增加主要在少突胶质细胞和星形胶质细胞中，而ST 2主要在星形胶质细胞中表达。进一步研究表明，在ACD小鼠中，St 2（-/-）显著减弱星形胶质细胞的活化和信号转导子和转录激活子3（STAT 3）的磷酸化增加。鞘内注射Janus激酶2抑制剂AG 490可显著减轻ACD小鼠的抓挠行为。rIL-33预处理加重了胃泌素释放肽（GRP）诱发的抓挠行为。这种增加的胃泌素释放肽受体（GRPR）表达被St 2（-/-）消除。St 2（-/-）可抑制TNF-α的上调。我们的研究结果表明，脊髓IL-33/ST 2信号通路通过星形胶质细胞JAK 2-STAT 3级联激活，促进TNF-α释放，调节GRP/GRPR信号相关的瘙痒反应，从而促进慢性瘙痒。因此，这些发现为治疗慢性瘙痒症提供了潜在的治疗选择。
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-alpha 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-alpha release to regulate the GRP/GRPR signaling-related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.