Febrile temperature-regulated TRPV1 in CD4(+) T cells mediates neuroinflammation in complex febrile seizures.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.