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

ABSTRACT: 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-1β 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-1β maturation in microglia is mediated by the cathepsin C–caspase-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-1β maturation may therefore be druggable targets in some forms of cognitive impairment. These insights identify a new intercellular microglia–neuron crosstalk and identify potential therapeutic targets to combat inflammasome-induced neuronal dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE218613 | GEO | 2022/11/26

REPOSITORIES: GEO

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Project description:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.

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

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