Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China.
Department of Immunology, Nanjing Medical University, Nanjing, People's Republic of China.
Glia. 2019 Sep;67(9):1680-1693. doi: 10.1002/glia.23639. Epub 2019 May 14.
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.
白细胞介素-33（IL-33）及其受体 ST2 有助于脊髓胶质细胞的激活和慢性疼痛。最近的一项研究表明，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 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 可显著减少二硝基氟苯（DNFB）诱导的过敏性接触性皮炎（ACD）以及丙酮和二乙醚随后水诱导的干燥皮肤小鼠的搔抓行为。鞘内给予中和抗 ST2 或抗 IL-33 抗体可显著减少 DNFB 诱导的 ACD 小鼠的搔抓反应。ACD 小鼠脊髓中 IL-33 和 ST2 的表达显著增加，表现为 mRNA 和蛋白水平增加。免疫荧光和原位杂交表明，脊髓中 IL-33 的表达增加主要发生在少突胶质细胞和星形胶质细胞中，而 ST2 主要表达在星形胶质细胞中。进一步的研究表明，在 ACD 小鼠中，St2 明显减弱了星形胶质细胞的激活和信号转导和转录激活因子 3（STAT3）的磷酸化。鞘内注射 Janus 激酶 2 抑制剂 AG490 可显著缓解 ACD 小鼠的搔抓行为。rIL-33 预处理加剧了胃泌素释放肽（GRP）引起的搔抓行为。这种增加的胃泌素释放肽受体（GRPR）表达被 St2 消除。TNF-α 的上调被 St2 抑制。我们的研究结果表明，脊髓 IL-33/ST2 信号通路通过星形胶质细胞 JAK2-STAT3 级联激活促进 TNF-α 释放来调节 GRP/GRPR 信号相关的瘙痒反应，从而导致慢性瘙痒。因此，这些发现为治疗慢性瘙痒提供了一种潜在的治疗选择。
