The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia.
The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia.
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DOI：
10.1038/s41598-021-94565-y
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发表时间：
2021-07-23
影响因子：
4.6
通讯作者：
Mak RH
中科院分区：
文献类型：
--
作者：
Cheung WW;Zheng R;Hao S;Wang Z;Gonzalez A;Zhou P;Hoffman HM;Mak RH
细胞因子如IL-6、TNF-α和IL-1 β触发炎症级联反应，其可能在慢性肾脏病（CKD）相关恶病质的发病机制中发挥作用。采用5/6肾切除法诱导小鼠慢性肾脏病模型。我们研究了Il1 β −/−/CKD、Il6 −/−/CKD和Tnf α −/−/CKD小鼠的能量稳态，并与野生型（WT）/CKD对照组进行了比较。恶病质表型参数在Il1 β −/−/CKD小鼠中完全正常化，但在Il6 −/−/CKD和Tnf α −/−/CKD小鼠中仅部分恢复。我们测试了阿那白滞素（一种IL-1受体拮抗剂）对CKD相关恶病质的影响。WT/CKD小鼠用阿那白滞素（2.5mg/kg/天，IP）或盐水处理6周，并与WT/假对照进行比较。阿那白滞素使WT/CKD小鼠的食物摄入量和体重增加、脂肪和瘦肉含量、代谢率和肌肉功能正常化，并且还减弱了脂肪组织和肌肉中能量稳态的分子扰动。阿那白滞素降低WT/CKD小鼠血清和肌肉中IL-6、TNF-α和IL-1 β的表达。阿那白滞素减弱WT/CKD小鼠中白色脂肪组织的布朗宁。此外，阿那白滞素使WT/CKD小鼠的腓肠肌重量和纤维大小正常化，并减弱肌肉脂肪浸润。这伴随着纠正增加的肌肉萎缩信号通路，同时促进WT/CKD小鼠腓肠肌中减少的肌生成过程。我们对WT/CKD小鼠与对照小鼠中先前通过RNAseq分析鉴定的前20个差异表达的肌肉基因进行了qPCR分析。重要的是，17个差异表达的肌肉基因在阿那白滞素治疗的WT/CKD小鼠中减弱。总之，IL-1受体拮抗剂可能是一种新的针对CKD脂肪组织布朗宁和肌肉萎缩的靶向治疗。
Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β−/−/CKD, Il6−/−/CKD and Tnfα−/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β−/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα−/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.
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DOI：
10.1084/jem.20111020
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Braun TP;Zhu X;Szumowski M;Scott GD;Grossberg AJ;Levasseur PR;Graham K;Khan S;Damaraju S;Colmers WF;Baracos VE;Marks DL
通讯作者：
Marks DL
影响因子：
3.8
作者：
Ballak DB;Stienstra R;Tack CJ;Dinarello CA;van Diepen JA
通讯作者：
van Diepen JA
影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
影响因子：
3.5
作者：
Huang N;Kny M;Riediger F;Busch K;Schmidt S;Luft FC;Slevogt H;Fielitz J
通讯作者：
Fielitz J
影响因子：
3.5
作者：
Busquets, S;Almendro, V;López-Soriano, FJ
通讯作者：
López-Soriano, FJ