STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch
STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch
复制标题
DOI：
10.1038/nm.3912
复制
发表时间：
2015-08-01
期刊：
影响因子：
82.9
通讯作者：
Tsuda, Makoto
中科院分区：
文献类型：
--
作者：
Shiratori-Hayashi, Miho;Koga, Keisuke;Tsuda, Makoto
慢性瘙痒是炎症性皮肤病的一种顽固性症状，如特应性皮炎和接触性皮炎（1-3）。最近的研究揭示了瘙痒的神经元选择性通路（4-8），但瘙痒转变为病理性慢性状态的机制知之甚少。使用小鼠模型的特应性和接触性皮炎，我们证明了一个长期的反应状态的星形胶质细胞在脊髓节段的背角，对应于病变，发痒的皮肤。我们发现反应性星形胶质细胞增生依赖于信号转导和转录激活因子3（STAT 3）的激活。星形胶质细胞STAT 3的条件性破坏抑制慢性瘙痒，脊髓STAT 3的药理学抑制改善了完全发展的慢性瘙痒。通过鞘内注射瘙痒诱导剂胃泌素释放肽（GRP）（4），特应性皮炎小鼠出现抓挠增加，这种增强通过抑制STAT 3介导的反应性星形胶质细胞增生而正常化。此外，我们确定了脂质运载蛋白-2（LCN 2）作为一种星形胶质细胞STAT 3依赖性上调因子，对慢性瘙痒至关重要，并且我们证明了鞘内注射LCN 2对正常小鼠增加了脊髓GRP诱发的抓挠。我们的研究结果表明，STAT 3依赖性反应性星形胶质细胞通过涉及LCN 2增强脊髓瘙痒信号的机制作为瘙痒的关键放大器，从而为治疗慢性瘙痒提供了以前未被认识到的靶点。
Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis(1-3). Recent studies have revealed neuronal pathways selective for itch(4-8), but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP)(4), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.