Noncanonical Il-1β maturation in microglia impairs cognition in chronic kidney disease via neuronal IL-1R signaling
Research Square (Research Square)(2023)
摘要
Abstract While cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD), mechanistic insights and effective therapies are lacking 1,2 . Organ substitution reverses cognitive impairment, indicating that cognitive impairment driven by peripheral diseases is therapeutically amendable 3,4 . Yet, we lack pharmacological approaches. Here, we show that despite inflammasome activation in the brain and protection in full body NLRP3-inflammasome deficient mice, microglial caspase-1 deficiency does not improve inflammation and cognition in CKD mice. Microglial potassium (K + ) dyshomeostasis induces noncanonical, cathepsin C–caspase-8 mediated IL-1β maturation and neuronal dysfunction via IL-1R signaling in CKD. Neuronal IL-1R-signaling induces neuronal NLRP3 expression, indicating an unrecognized function of NLRP3 in neurons. Restoring K + homeostasis in microglia using a K Ca 3.1-specific inhibitor (TRAM34) or genetically inhibiting neuronal IL-1R1 signaling improves CKD-triggered cognitive impairment. These insights identify a new intercellular microglia IL-1β –neuron IL-1R1 crosstalk and identify potential therapeutic targets to combat neuronal dysfunction in peripheral diseases.
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关键词
microglia impairs cognition,chronic kidney disease,kidney disease
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