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bioRxiv · 10.64898/2026.05.26.725945

A post-inflammatory C3-high astrocyte state persists after inflammatory stimulus withdrawal and is attenuated by JAK inhibition

Sakakibara, Y.·Okahara, K.·Kakuta, J.·Emoto, K.·Ofusa, Y.·Ohba, K.
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Abstract

Reactive astrocytes contribute to neuroinflammation and synaptic dysfunction, but it remains unclear whether transient inflammatory stimulation causes a persistent reactive state after the initial inflammatory stimulus is removed. Here, we investigated whether transient exposure to a defined inflammatory cytokine/complement cocktail induces a persistent reactive astrocyte state and examined the signaling mechanism underlying its maintenance. Human astrocytes were exposed to the inflammatory stimulus and subsequently subjected to stimulus washout, followed by time-course analyses to compare the reversibility of inflammatory gene expression after stimulus removal. Following washout, the expression of several inflammatory response genes, including CXCL10 and NF-{kappa}B-associated genes such as NFKBIA, TNFAIP3, and RELB, returned toward baseline levels. In contrast, C3 expression remained elevated, indicating persistence of a post-inflammatory C3-high astrocyte state after withdrawal of the inflammatory stimulus. Pharmacological inhibition of JAK signaling reduced persistent C3 expression to near-baseline levels, supporting the involvement of JAK-dependent signaling in maintenance of this persistent state. Together, these findings suggest that transient inflammatory stimulation induces a post-inflammatory persistent C3-high astrocyte state that is maintained even after broader inflammatory gene responses have subsided. This persistent C3-high component is pharmacologically attenuated by JAK inhibition, identifying JAK-dependent pathways as modulators of persistent astrocyte inflammatory reactivity.

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Sakakibara, Y., Okahara, K., Kakuta, J., Emoto, K., Ofusa, Y., Ohba, K.. 2026-05-28. A post-inflammatory C3-high astrocyte state persists after inflammatory stimulus withdrawal and is attenuated by JAK inhibition. https://doi.org/10.64898/2026.05.26.725945

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