Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025
Noncanonical microglial IL-1β maturation in chronic kidney disease.
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Zimmermann Silke, Mathew Akash, Bondareva Olga, Elwakiel Ahmed, Jiang Shihai, Rana Rajiv, Bechmann Ingo, Goldschmidt Jürgen, Klöting Nora, Sheikh Bilal N, Isermann Berend
Аннотация
BACKGROUND: 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 interleukin-1β (IL-1β) release from microglia and IL-1 receptor type 1 signalling in neuronal cells, thereby identifying a signalling 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 cross-talk between microglia and neurons that impairs cognition in 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, caspase-1 is not required for IL-1β maturation in microglia and 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 possibly other peripheral diseases.
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 cross-talk between microglia and neurons that impairs cognition in 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, caspase-1 is not required for IL-1β maturation in microglia and 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 possibly other peripheral diseases.