慢性肾病中的非典型小胶质细胞 IL-1β 成熟

IF 4.8 2区 医学 Q1 TRANSPLANTATION Nephrology Dialysis Transplantation Pub Date : 2024-11-04 DOI:10.1093/ndt/gfae239
Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Shihai Jiang, Rajiv Rana, Ingo Bechmann, Jürgen Goldschmidt, Nora Klöting, Bilal N Sheikh, Berend Isermann
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引用次数: 0

摘要

背景与假设:器官移植可逆转慢性肾脏病(CKD)的认知障碍,这表明由慢性肾脏病引起的认知障碍是可以治疗的。我们最近证明,CKD 患者的认知功能受损与小胶质细胞释放 IL-1β 和神经元细胞中的 IL-1R1 信号有关,从而确定了一条可用于治疗的信号通路。然而,IL-1β在CKD小胶质细胞中的成熟机制仍然未知。我们假设,小胶质细胞在 CKD 驱动的认知障碍中需要 caspase-1:我们综合使用了单细胞分析、原位分析、转基因小鼠模型(包括新生成的 Cre-LoxP 小鼠模型)和体外模型。目前的研究以最近发现的小胶质细胞和神经元之间的细胞间串扰为基础,这种串扰会损害慢性肾脏病(CKD)患者的认知能力:结果:我们在这里发现,尽管大脑中的 NLRP3 炎性体被激活,并且构成性 NLRP3 缺乏的小鼠可免受 CKD 诱导的认知障碍的影响,但(i) 小胶质细胞中的 IL-1β 成熟并不需要 caspase-1;(ii) 小胶质细胞中 caspase-1 的靶向缺乏并不能改善 CKD 小鼠的认知能力。这些数据表明,在 CKD 中,IL-1β 在小胶质细胞中的成熟与 NLRP3-caspase-1 相互作用无关。事实上,CKD 中的小胶质细胞激活会诱导非典型的、由 cathepsin C-caspase-8 介导的 IL-1β 成熟。消耗掉 cathepsin C 或 caspase-8 会阻止 IL-1β 在小胶质细胞中的成熟。初步分析表明,非典型的小胶质细胞IL-1β成熟也发生在糖尿病患者中:这些结果确定了非典型 IL-1β 成熟途径是一种潜在的治疗靶点,可用于对抗 CKD 和其他可能的外周疾病中由小胶质细胞诱导的神经元功能障碍。
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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.

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来源期刊
Nephrology Dialysis Transplantation
Nephrology Dialysis Transplantation 医学-泌尿学与肾脏学
CiteScore
10.10
自引率
4.90%
发文量
1431
审稿时长
1.7 months
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.
期刊最新文献
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