Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Shihai Jiang, Rajiv Rana, Ingo Bechmann, Jürgen Goldschmidt, Nora Klöting, Bilal N Sheikh, Berend Isermann
{"title":"慢性肾病中的非典型小胶质细胞 IL-1β 成熟","authors":"Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Shihai Jiang, Rajiv Rana, Ingo Bechmann, Jürgen Goldschmidt, Nora Klöting, Bilal N Sheikh, Berend Isermann","doi":"10.1093/ndt/gfae239","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and hypothesis: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Noncanonical microglial IL-1β maturation in chronic kidney disease.\",\"authors\":\"Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Shihai Jiang, Rajiv Rana, Ingo Bechmann, Jürgen Goldschmidt, Nora Klöting, Bilal N Sheikh, Berend Isermann\",\"doi\":\"10.1093/ndt/gfae239\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and hypothesis: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":19078,\"journal\":{\"name\":\"Nephrology Dialysis Transplantation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nephrology Dialysis Transplantation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/ndt/gfae239\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"TRANSPLANTATION\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nephrology Dialysis Transplantation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ndt/gfae239","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"TRANSPLANTATION","Score":null,"Total":0}
Noncanonical microglial IL-1β maturation in chronic kidney disease.
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.
期刊介绍:
Nephrology Dialysis Transplantation (ndt) is the leading nephrology journal in Europe and renowned worldwide, devoted to original clinical and laboratory research in nephrology, dialysis and transplantation. ndt is an official journal of the [ERA-EDTA](http://www.era-edta.org/) (European Renal Association-European Dialysis and Transplant Association). Published monthly, the journal provides an essential resource for researchers and clinicians throughout the world. All research articles in this journal have undergone peer review.
Print ISSN: 0931-0509.