Kong Shuo, Jia Xianglei, Liang Xin, Chen Yu, Liang Jingyi, Zhang Yan, Wu Ningyang, Su Song, Chen Taoxiang, He Xiaohua, Yin Jun, Han Song, Liu Wanhong, Fan Yuanteng, Xu Jian, Peng Biwen
Department of Physiology, Wuhan University School of Basic Medical Sciences, 185 Donghu Road, Wuhan, 430071, Hubei, China.
Department of Genetics, Shandong Second Medical University, Weifang, 261053, China.
J Neuroinflammation. 2025 Apr 7;22(1):103. doi: 10.1186/s12974-025-03421-7.
Febrile seizures (FS) are the most prevalent convulsive disorder in children characterized by a high recurrence rate. However, the interaction between adaptive and innate immunity in the recurrence of FS remains poorly understood, and the molecular pathways involved are unclear. The objective of this study is to elucidate the role of Th17 cells in seizure susceptibility following complex febrile seizures (CFS), and to explore the regulatory mechanisms underlying Th17 cell differentiation and function under hyperthermic conditions through transient receptor potential vanilloid 1 (TRPV1).
RNA sequencing was employed to validate the seizure susceptibility following CFS and to explore the potential mechanisms by which high temperature contributes to Th17 cell differentiation. Neuronal excitability and damage were examined using Multi-electrode array (MEA) analysis and Nissl staining. Flow cytometry, chromatin immunoprecipitation (ChIP) analysis, and immunofluorescence (IF) were applied to examine how TRPV1 facilitates Th17 cell differentiation.
Our study demonstrates that proinflammatory Th17 cells exhibit enhanced differentiation in a CFS mouse model and exacerbate blood-brain barrier (BBB) disruption. After infiltrating the central nervous system (CNS), Th17 cells promote neuroinflammation by activating microglia via IL-17A. Mechanistically, TRPV1 is critical for Th17 cell differentiation and function. Activated by febrile temperature both in vivo and in vitro, TRPV1 facilitates calcium ion influx, leading to the nuclear localization of nuclear factor of activated T cell 2 and 4 (NFAT2/4) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Knockdown of TRPV1 attenuates Th17 cell differentiation and CNS infiltration, thereby protecting the BBB and reducing seizure susceptibility following CFS.
These results highlight the critical interplay between adaptive and innate immunity in CFS. The TRPV1/NFATs/STAT3 signaling pathway regulates Th17 cell differentiation and function under febrile conditions, revealing a promising therapeutic target for intervention.
热性惊厥（FS）是儿童中最常见的惊厥性疾病，其特征是复发率高。然而，适应性免疫和先天性免疫在FS复发中的相互作用仍知之甚少，且涉及的分子途径尚不清楚。本研究的目的是阐明Th17细胞在复杂性热性惊厥（CFS）后癫痫易感性中的作用，并通过瞬时受体电位香草酸受体1（TRPV1）探索高温条件下Th17细胞分化和功能的调节机制。
采用RNA测序来验证CFS后的癫痫易感性，并探索高温促进Th17细胞分化的潜在机制。使用多电极阵列（MEA）分析和尼氏染色检查神经元兴奋性和损伤情况。采用流式细胞术、染色质免疫沉淀（ChIP）分析和免疫荧光（IF）来检测TRPV1如何促进Th17细胞分化。
我们的研究表明，促炎性Th17细胞在CFS小鼠模型中表现出增强的分化，并加剧血脑屏障（BBB）破坏。Th17细胞浸润中枢神经系统（CNS）后，通过IL-17A激活小胶质细胞来促进神经炎症。机制上，TRPV1对Th17细胞的分化和功能至关重要。在体内和体外，TRPV1均被发热温度激活，促进钙离子内流，导致活化T细胞核因子2和4（NFAT2/4）的核定位以及信号转导和转录激活因子3（STAT3）的磷酸化。敲低TRPV1可减弱Th17细胞分化和CNS浸润，从而保护BBB并降低CFS后的癫痫易感性。
这些结果突出了CFS中适应性免疫和先天性免疫之间的关键相互作用。TRPV1/NFATs/STAT3信号通路在发热条件下调节Th17细胞的分化和功能，揭示了一个有前景的干预治疗靶点。
