血小板衍生血清素激活SST⁺ 受体通过5HTR2B介导UVB诱导的瘙痒
Platelet-Derived serotonin activates SST⁺ pruriceptors via 5HTR2B to mediate UVB-Induced itch.
摘要(中文译文)
紫外线B（UVB）辐射是瘙痒的主要环境触发因素，从轻微的晒伤相关瘙痒到难以忍受的“地狱之痒”，然而连接UVB与持续搔抓的神经免疫通路仍知之甚少。除了在止血和炎症中的传统作用外，血小板正逐渐被认为是神经免疫信号传导的关键调节因子。然而，血小板是否直接影响病理性和瘙痒中的感觉神经元活动仍不清楚。本研究探讨血小板在UVB诱导的瘙痒中的作用，重点关注5-HT信号传导和神经元亚型。我们采用了多模式实验方法，包括UVB照射后人类和小鼠皮肤的转录组分析、通过Pf4; iDTR小鼠进行血小板清除、血小板光遗传学操控（Pf4; Ai32）、离体皮肤-神经记录、药理学抑制、基因敲除模型（Tph1、Slc6a4、5Htr2b）、血小板谱系示踪（Pf4; Ai9）、背根神经节神经元的单细胞RNA测序以及条件性基因敲除策略（Cre-loxP）。通过行为学、电生理学、分子学和组织学评估来验证关键机制。转录组分析揭示UVB照射皮肤中血小板活化和聚集通路上调。我们证明血小板浸润发生于UVB照射皮肤中，并与感觉神经纤维密切相关。选择性血小板清除显著减弱了自发性瘙痒行为，而未改变炎症反应。此外，外周5-HT合成/摄取或5HTR2B信号的药理学抑制，以及Tph1、Slc6a4或5Htr2b的基因敲除，均抑制了瘙痒行为。scRNA-seq和免疫组化鉴定生长抑素阳性（SST⁺）感觉神经元为主要的5HTR2B表达靶标；SST⁺神经元中条件性5Htr2b缺失重现了瘙痒减轻表型，证实外周5-HT释放及通过SST⁺神经元上5HTR2B的信号传导对于瘙痒传递至关重要。我们的发现揭示了一个新型血小板-神经元轴，其中血小板来源的5-HT通过5HTR2B直接激活SST⁺瘙痒感受器，从而介导UVB诱导的瘙痒。该通路代表了UVB相关及慢性瘙痒性疾病的一个有前景的治疗靶点，推进了我们对皮肤神经免疫交互的理解。
Abstract
Ultraviolet B (UVB) radiation is a major environmental trigger of pruritus, from mild sunburn-associated itch to the excruciating Hell's itch, yet the neuroimmune wiring connecting UVB to relentless scratching remains poorly understood. Beyond their traditional roles in hemostasis and inflammation, platelets emerging as key modulators of neuroimmune signaling. However, whether platelets directly influence sensory neuron activity in pathological itch remains unknown. This study explores platelets' role in UVB-induced itch, focusing on 5-HT signaling and neuronal subtypes. We employed a multimodal experimental approach, including transcriptomic analysis of UVB-irradiated human and mouse skin, platelet depletion via Pf4; iDTR mice, optogenetic manipulation of platelets (Pf4; Ai32), ex vivo skin-nerve recordings, pharmacological inhibition, genetic knockout models (Tph1, Slc6a4, 5Htr2b), lineage tracing of platelets (Pf4; Ai9), single-cell RNA sequencing of dorsal root ganglion neurons, and conditional knockout strategies (Cre-loxP). Behavioral, electrophysiological, molecular, and histological assessments were performed to validate the key mechanisms. Transcriptomic analysis revealed upregulated platelet activation and aggregation pathways in UVB-irradiated skin. We demonstrated platelet infiltration occurs in UVB-irradiated skin and is closely associated with sensory nerve fibers. Selective platelet depletion significantly attenuated spontaneous itch behavior without altering inflammatory responses. Moreover, Pharmacological inhibition of peripheral 5-HT synthesis/uptake or 5HTR2B signaling, as well as genetic knockout of Tph1, Slc6a4, or 5Htr2b, suppressed itch behavior. scRNA-seq and immunohistochemistry identified somatostatin-positive (SST⁺) sensory neurons as the primary 5HTR2B-expressing targets; conditional 5Htr2b deletion in SST⁺ neurons recapitulated the itch-reduction phenotype, confirming that peripheral 5-HT release and signaling through 5HTR2B on SST⁺ neurons are essential for itch transmission. Our findings uncover a novel platelet-neuron axis wherein platelet-derived 5-HT directly activates SST⁺ pruriceptors via the 5HTR2B to mediate UVB-induced itch. This pathway represents a promising therapeutic target for UVB-related and chronic pruritic disorders, advancing our understanding of cutaneous neuroimmune crosstalk.
如何引用
AMA
Ximin Hu, Ting Wang, Lixia Du, Xiaoying Zhang, Jinghan Liu, Jialin Su, et al. Platelet-Derived serotonin activates SST⁺ pruriceptors via 5HTR2B to mediate UVB-Induced itch.. Journal of advanced research. 2026; doi:10.1016/j.jare.2026.05.018.
APA
Ximin Hu, Ting Wang, Lixia Du, Xiaoying Zhang, Jinghan Liu, Jialin Su, et al (2026). Platelet-Derived serotonin activates SST⁺ pruriceptors via 5HTR2B to mediate UVB-Induced itch.. Journal of advanced research. https://doi.org/10.1016/j.jare.2026.05.018
GB/T 7714
Ximin Hu, Ting Wang, Lixia Du, Xiaoying Zhang, Jinghan Liu, Jialin Su, et al. Platelet-Derived serotonin activates SST⁺ pruriceptors via 5HTR2B to mediate UVB-Induced itch.[J]. Journal of advanced research, 2026 doi:10.1016/j.jare.2026.05.018.
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