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We recently demonstrated that impaired cognition in CKD is linked to interleukin-1\u03b2 (IL-1\u03b2) 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-1\u03b2 maturation in microglia in CKD remains unknown. We hypothesized that microglia cells require caspase-1 for CKD-driven cognitive impairment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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-1\u03b2 maturation in microglia and targeted caspase-1 deficiency in microglia does not improve cognition in CKD mice. These data indicate that IL-1\u03b2 maturation in microglia is independent of the NLRP3\u2013caspase-1 interaction in CKD. Indeed, microglia activation in CKD induces noncanonical, cathepsin C\u2013caspase-8\u2013mediated IL-1\u03b2 maturation. Depletion of cathepsin C or caspase-8 blocks IL-1\u03b2 maturation in microglia. Preliminary analyses suggest that noncanonical microglia IL-1\u03b2 maturation occurs also in diabetes mellitus.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results identify a noncanonical IL-1\u03b2-maturation pathway as a potential therapeutic target to combat microglia-induced neuronal dysfunction in CKD and possibly other peripheral diseases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfae239","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T02:41:12Z","timestamp":1730774472000},"page":"929-942","source":"Crossref","is-referenced-by-count":2,"title":["Noncanonical microglial IL-1\u03b2 maturation in chronic kidney 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