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Noncanonical microglial IL-1β maturation in chronic kidney disease.
Nephrol. Dial. Transplant.:gfae239 (2024)
BACKGROUND AND HYPOTHESIS: Organ transplantation reverses cognitive impairment in chronic kidney disease (CKD), indicating that cognitive impairment driven by CKD is therapeutically amendable. We recently demonstrated that impaired cognition in CKD is linked to IL-1β-release from microglia and IL-1R1-signaling in neuronal cells, thereby identifying a signaling pathway that can be exploited therapeutically. However, the mechanism of IL-1β-maturation in microglia in CKD remains unknown. We hypothesized that microglia cells require caspase-1 for CKD-driven cognitive impairment. METHODS: We used a combination of single cell analyses, in situ analyses, genetically modified mouse models (including newly generated Cre-LoxP mouse models) and in vitro models. The current study builds on a recently identified intercellular crosstalk between microglia and neurons that impairs cognition in chronic kidney disease (CKD). RESULTS: Here, we show that despite NLRP3 inflammasome activation in the brain and protection of mice with constitutive NLRP3 deficiency from CKD-induced cognitive impairment, (i) caspase-1 is not required for IL-1β maturation in microglia and (ii) targeted caspase-1 deficiency in microglia does not improve cognition in CKD mice. These data indicate that IL-1β maturation in microglia is independent of the NLRP3-caspase-1 interaction in CKD. Indeed, microglia activation in CKD induces noncanonical, cathepsin C-caspase-8 mediated IL-1β maturation. Depletion of cathepsin C or caspase-8 blocks IL-1β maturation in microglia. Preliminary analyses suggest that noncanonical microglia IL-1β maturation occurs also in diabetes mellitus. CONCLUSION: These results identify a noncanonical IL-1β-maturation pathway as a potential therapeutic target to combat microglia-induced neuronal dysfunction in CKD and possible other peripheral diseases.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Caspase-8 ; Cathepsins ; Chronic Diseases ; Cognition ; Inflammation ; Microglia Signaling; Diabetic-nephropathy; Nlrp3 Inflammasome; Oxidative Stress; Activation; Pathology; Cirrhosis; Pathway; Injury
ISSN (print) / ISBN
0931-0509
e-ISSN
1460-2385
Quellenangaben
Article Number: gfae239
Publisher
Oxford University Press
Publishing Place
Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants
Medical Faculty of the University of Leipzig
Deutscher Akademischer Austauschdienst
DFG
German Research Foundation)
Deutsche Forschungsgemeinschaft (DFG
Deutscher Akademischer Austauschdienst
DFG
German Research Foundation)
Deutsche Forschungsgemeinschaft (DFG