RGED RGED / Noncanonical Il-1 maturation in microglia impairs cognition in chronic kidney disease via neuronal IL1R signaling

Public on 2022-11-23

Description

While cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD), mechanistic insights and effective therapies are lacking. Here, we show that microglial potassium (K+) dyshomeostasis induces noncanonical IL-1 maturation and neuronal dysfunction via IL-1R signaling in CKD. Despite inflammasome activation in the brain, microglial caspase-1 deficiency does not improve inflammation and cognition in CKD mice. Noncanonical IL-1 maturation in microglia is mediated by the cathepsin Ccaspase-8 pathway. Restoring K+ homeostasis in microglia or genetically inhibiting neuronal IL-1R1 signaling abolishes CKD-induced cognitive impairment. Microglial K+ dyshomeostasis and noncanonical microglial IL-1 maturation may therefore be druggable targets in some forms of cognitive impairment. These insights identify a new intercellular microglianeuron crosstalk and identify potential therapeutic targets to combat inflammasome-induced neuronal dysfunction.

Overall Design

We performed single nuclei RNAseq in order to investigate gene expression profiling in brain cells of the cortex in chronic kidney disease versus control/sham mice.

Curator

yq_pan

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