Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice,Journal of Allergy and Clinical Immunology

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Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-08-08 , DOI: 10.1016/j.jaci.2020.06.039
Miho Shiratori-Hayashi ₁ , Chiharu Yamaguchi ₁ , Kazushi Eguchi ₁ , Yuto Shiraishi ₁ , Keita Kohno ₁ , Katsuhiko Mikoshiba ₂ , Kazuhide Inoue ₃ , Motohiro Nishida ₄ , Makoto Tsuda ₁

Affiliation

Background

Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.

Objective

We aimed to determine the mechanisms of persistent activation of astrocytic STAT3 in chronic itch conditions.

Methods

To determine the factors that are required for persistent activation of astrocytic STAT3, Western blotting and calcium imaging with cultured astrocytes or spinal cord slices were performed. Thereafter, chronic itch model mice were used for genetic and behavioral experiments to confirm the role of the factors determined to mediate persistent STAT3 activation from in vitro and ex vivo experiments in chronic itch.

Results

IP₃ receptor type 1 (IP₃R1) knockdown in astrocytes suppressed IL-6–induced persistent STAT3 activation and expression of lipocalin-2 (LCN2), an astrocytic STAT3-dependent inflammatory factor that is required for chronic itch. IP₃R1-dependent astrocytic Ca²⁺ responses involved Ca²⁺ influx through the cation channel transient receptor potential canonical (TRPC), which was required for persistent STAT3 activation evoked by IL-6. IL-6 expression was upregulated in dorsal root ganglion neurons in a mouse model of chronic itch. Dorsal root ganglion neuron–specific IL-6 knockdown, spinal astrocyte–specific IP₃R1 knockdown, and pharmacologic spinal TRPC inhibition attenuated LCN2 expression and chronic itch.

Conclusion

Our findings suggest that IP₃R1/TRPC channel–mediated Ca²⁺ signals elicited by IL-6 in astrocytes are necessary for persistent STAT3 activation, LCN2 expression, and chronic itch, and they may also provide new targets for therapeutic intervention.

中文翻译：

小鼠中星形胶质细胞 STAT3 激活和慢性瘙痒需要 IP3R1/TRPC 依赖性 Ca2+ 信号

背景

慢性瘙痒是炎症性皮肤病的一种令人衰弱的症状，但其潜在机制尚不清楚。我们最近证明，在特应性皮炎和接触性皮炎模型中，脊髓背角的星形胶质细胞通过转录因子信号转导器和转录激活剂 3 (STAT3) 的激活而发生反应，并对慢性瘙痒起到关键作用。一般情况下，STAT3是短暂激活的；然而，慢性瘙痒模型小鼠的反应性星形胶质细胞中的 STAT3 激活通过未知机制持续发生。

客观的

我们的目的是确定慢性瘙痒条件下星形细胞 STAT3 持续激活的机制。

方法

为了确定星形胶质细胞 STAT3 持续激活所需的因素，使用培养的星形胶质细胞或脊髓切片进行了蛋白质印迹和钙成像。此后，使用慢性瘙痒模型小鼠进行遗传和行为实验，以确认体外和离体实验确定的介导持久性STAT3激活的因素在慢性瘙痒中的作用。

结果

星形胶质细胞中 IP ₃受体 1 型 (IP ₃ R1) 敲低抑制了 IL-6 诱导的持续 STAT3 激活和脂质运载蛋白-2 (LCN2) 的表达，脂质运载蛋白-2 是慢性瘙痒所需的星形胶质细胞 STAT3 依赖性炎症因子。 IP ₃ R1 依赖性星形细胞 Ca ²⁺反应涉及 Ca ²⁺通过阳离子通道瞬时受体电位经典 (TRPC) 流入，这是 IL-6 诱发持续 STAT3 激活所必需的。在慢性瘙痒小鼠模型中，背根神经节神经元中 IL-6 的表达上调。背根神经节神经元特异性 IL-6 敲低、脊髓星形胶质细胞特异性 IP ₃ R1 敲低和药物脊髓 TRPC 抑制减弱了 LCN2 表达和慢性瘙痒。