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Neuroinflammation within the central nervous system (CNS) is recognized as a critical pathological process in meningitic Escherichia coli (E. coli) infection, leading to severe neurodegenerative disorders and long-term sequelae. Astrocyte reactivity plays a pivotal role in driving the neuroinflammatory cascade in response to pathological stimuli from peripheral sources or other cellular components of the CNS. The involvement of astrocyte reactivity in the inflammatory process induced by bacterial infection within the CNS warrants further investigation. In this study, we observed an astrocyte reaction likely mediated by brain microvascular endothelial cells (BMEC) during meningitic E. coli infection in both a mouse model and a BMEC-astrocyte coculture system. Through label-free quantitative proteomics analysis of the BMEC secretome, we identified CK2 as a potential trigger for astrocyte reactivity. Inhibition of CK2 attenuated the reaction of hippocampal astrocytes in E. coli meningitis. Furthermore, we demonstrated that CK2 enhances NF-κB activation via its interaction with myosin 9, thereby increasing astrocyte reactivity and the inflammatory response both in vivo and in vitro. By conditionally knocking out CK2β in microvessel, we blocked CK2 secretion, resulting in reduced astrocyte reactivity and neuroinflammation during the early stages of infection. Compared to wild-type mice, CK2βVas-/- mice exhibited a significantly higher survival rate. Collectively, our findings highlight the essential role of endothelial-glial communication mediated by CK2 interaction with myosin 9 in activating the downstream NF-κB pathway, contributing to astrocyte reactivity and neuroinflammation. These results provide novel insights into the treatment of CNS inflammation caused by bacterial blood-borne infections.
Huo et al. (Wed,) studied this question.