It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

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Vascular endothelial cells (ECs) are monolayer cells located in the inner layer of the blood vessel. Endothelial function is crucial in maintaining local and systemic homeostasis and is precisely regulated by sophisticated signaling pathways and epigenetic regulation. Endothelial dysfunctions are the main factors for the pathophysiological process of cardiovascular and cerebrovascular diseases like atherosclerosis, hypertension, and stroke. In these pathologic processes, histone deacetylases (HDACs) involve in epigenetic regulation by removing acetyl groups from lysine residues of histones and regulating downstream gene expression. Among all HDACs, Class IIa HDACs (HDAC4, 5, 7, 9) contain only an N-terminal regulatory domain, exert limited HDAC activity, and present tissue-specific gene regulation. Here, we discuss and summarize the current understanding of this distinct subfamily of HDACs in endothelial cell functions (such as angiogenesis and immune response) with their molecular underpinnings. Furthermore, we also present new thoughts for further investigation of HDAC inhibitors as a potential treatment in several vascular diseases.