STING restrains calcium-dependent microglial phagocytosis and protects against neuronal loss and cognitive impairment during epileptogenesis

Kasahara, Y.; Nakashima, H.; Miyashita, S.; Umeyama, T.; Nakano, Y.; Kumamoto, S.; Kawata, K.; Imabayashi, K.; Baba, Y.; Kobiyama, K.; Ishii, K. J.; Sato, T.; Johmura, Y.; Hoshino, M.; Nakashima, K.

doi:10.64898/2026.06.25.734646

bioRxiv · 10.64898/2026.06.25.734646

STING restrains calcium-dependent microglial phagocytosis and protects against neuronal loss and cognitive impairment during epileptogenesis

Kasahara, Y.·Nakashima, H.·Miyashita, S.·Umeyama, T.·Nakano, Y.·Kumamoto, S.·Kawata, K.·Imabayashi, K.·Baba, Y.·Kobiyama, K.·Ishii, K. J.·Sato, T.·Johmura, Y.·Hoshino, M.·Nakashima, K.

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Abstract

Epileptogenesis is accompanied by robust neuroinflammation, yet the molecular pathways linking innate immune activation to neuronal dysfunction remain incompletely defined. Given the established pro-inflammatory role of the stimulator of interferon genes (STING), we initially hypothesized that its loss would attenuate neuroinflammatory responses during epileptogenesis. Contrary to our expectation, we found that STING deficiency instead amplified microglial activation. Using a kainic acid mouse model of temporal lobe epilepsy (TLE), we show that STING-deficient microglia exhibit pronounced lysosomal expansion and enhanced phagocytic engulfment of neurons, leading to increased hippocampal neuronal loss and cognitive impairment. Mechanistically, STING deficiency increased the expression and altered the subcellular distribution of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca{superscript 2} sensor that mediates store-operated calcium entry (SOCE), resulting in dysregulated intracellular calcium dynamics and elevated SOCE activity. Pharmacological inhibition of SOCE reduced microglia-neuron interactions and microglial phagocytic engulfment, improved neuronal survival in the CA3 region of the hippocampus, and rescued cognitive deficits following status epilepticus. Collectively, these findings redefine STING as a negative regulator of microglial activation and identify a previously unrecognized STING-STIM1-SOCE axis that constrains calcium-dependent microglial phagocytosis during epileptogenesis, highlighting microglial calcium signaling as a potential therapeutic target in TLE.

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Kasahara, Y., Nakashima, H., Miyashita, S., Umeyama, T., Nakano, Y., Kumamoto, S., Kawata, K., Imabayashi, K., Baba, Y., Kobiyama, K., Ishii, K. J., Sato, T., Johmura, Y., Hoshino, M., Nakashima, K.. 2026-06-30. STING restrains calcium-dependent microglial phagocytosis and protects against neuronal loss and cognitive impairment during epileptogenesis. https://doi.org/10.64898/2026.06.25.734646

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