Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cells
Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cells
复制标题
DOI：
10.1172/jci126078
复制
发表时间：
2020-04-01
影响因子：
15.9
通讯作者：
Stranahan, Alexis M.
中科院分区：
文献类型：
--
作者：
Guo, De-Huang;Yamamoto, Masaki;Stranahan, Alexis M.
在内脏脂肪组织(VAT)中诱导炎症体蛋白低温比林(NLRP3)可促进肥胖症患者促炎细胞因子IL-1β的释放。尽管这一机制导致了外周代谢功能障碍，但对大脑的影响仍未被研究。我们研究了内脏脂肪NLRP3是否通过激活小胶质细胞IL-1受体1(IL-1R1)来损害认知。在观察了NLRP3-KO小鼠对肥胖引起的神经炎症和认知障碍的保护作用后，我们将肥胖的WT或NLRP3-KO供体的增值税移植到瘦小鼠体内。来自WT供者的VAT移植(TRAN(WT))增加了海马区IL-1β和认知损害，但来自肥胖的NLRP3-KO供者(TRAN(KO))的VAT移植没有影响。移植受者的长时程增强(LTP)缺陷需要内脏脂肪NLRP3，而反式(WT)小鼠的LTP损伤依赖于IL-1。流式细胞仪和基因表达分析显示，VAT移植重现了肥胖对小胶质细胞激活和IL-1β基因表达的影响，体内海马区小胶质细胞的可视化也显示了类似的效果。在表达CX3CR1的细胞中诱导消融IL-1R1可以消除饮食肥胖小鼠和移植受者的认知障碍，并恢复海马区小胶质细胞的免疫平静。这些结果表明，内脏脂肪NLRP3通过IL-1介导的小胶质细胞激活而损害记忆，提示NLRP3/1L-1β信号可能是内脏脂肪与人类认知障碍之间的相关性的基础。
Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the proinflammatory cytokine IL-1 beta in obesity. Although this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. We investigated whether visceral adipose NLRP3 impairs cognition by activating microglial IL-1 receptor 1 (IL-1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3-KO mice, we transplanted VAT from obese WT or NLRP3-KO donors into lean recipient mice. Transplantation of VAT from a WT donor (TRANS(WT)) increased hippocampal IL-1 beta and impaired cognition, but VAT transplants from comparably obese NLRP3-KO donors (TRANS(KO)) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANS(WT) mice was IL-1 dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL-1 beta gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL-1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL-1-mediated microglial activation and suggest that NLRP3/1L-1 beta signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.