Fig. 7: Model of RS218-induced death of BMECs. | Nature Communications

Fig. 7: Model of RS218-induced death of BMECs.

From: RIPK1 kinase drove brain microvascular endothelial cells death and blood-brain barrier disruption in neonatal Escherichia coli meningitis

Fig. 7

Under physiological conditions, the integrity of the BBB is maintained by endothelial cells, tight junctions, pericytes, the basement membrane, and astrocytes, effectively preventing macromolecules and pathogens from translocating from the bloodstream (top) into the brain (bottom). In E. coli meningitis, RS218 induced BMECs death through RIPK1 kinase-dependent and independent pathways. While caspase-8 limited programmed necrosis and pyroptosis by cleaving RIPK1 and suppressing caspase-1-ASC inflammasome formation, the death of membrane-compromised BMECs remained inevitable. This detrimental effect on BMECs directly compromised BBB integrity, facilitating RS218 penetration into brain tissue via the paracellular pathway. Pharmacological inhibition of RIPK1 kinase activity with Nec-1s effectively suppressed BMECs death and preserved RIPK1. The scaffolding function of RIPK1 was thus maintained, enhancing its ability to inhibit RIPK3-MLKL-mediated necroptosis. Ultimately, this mitigated BMECs death and BBB disruption.

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