IRF7-mediated microglia activation exacerbates temporal lobe epilepsy through targeting the neuronal RORB/STIM1 pathway

Temporal lobe epilepsy (TLE) is the most common and severe form of drug-resistant epilepsy. Glial cell-induced neuroinflammation is recognized as a key contributor to neuronal hyperexcitability in TLE. Previous studies utilizing single-cell sequencing have identified inflammatory responses in glial cells. However, no research has yet provided computational evidence to identify the major regulatory cell types and effector molecules involved in TLE. Our study constructed activated regulatory networks of TLE using single-nucleus RNA sequencing and identified interferon regulatory factor 7 (IRF7) in microglia as a key regulator of the TLE microenvironment, which leads to pro-inflammatory activation. By integrating microglia-neuron co-culture models and RNA sequencing, we revealed that IRF7 translocation and microglial IFN-β release contributed to neuronal injury. Notably, we highlight that microglia primarily interact with retinoic acid-related orphan receptor beta (RORB)-positive neurons and disrupt neuronal homeostasis by reducing RORB-mediated transcriptional activation of the stromal interaction molecule 1 (STIM1) through neuroinflammatory processes, thereby contributing to the epileptic phenotype. Our study positioned IRF7 as a central regulator of the TLE neuronal inflammation. It integrated IFN-related inflammation with neuronal RORB–STIM1 signaling to induce neuronal damage, suggesting that targeting IRF7 could be a potential neuroprotective therapy for TLE.