Mondal Ayan, Bose Dipro, Saha Punnag, Sarkar Sutapa, Seth Ratanesh, Kimono Diana, Albadrani Muayad, Nagarkatti Mitzi, Nagarkatti Prakash, Chatterjee Saurabh
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, 29208, USA.
Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
J Neuroinflammation. 2020 Jul 4;17(1):201. doi: 10.1186/s12974-020-01876-4.
Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology.
Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis.
Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β.
In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.
近期的临床和基础研究表明，非酒精性脂肪性肝病/非酒精性脂肪性肝炎（NAFLD/NASH）表型与包括神经炎症和神经退行性变在内的异位表现之间存在密切关联，但其中涉及的介质和关键途径尚不清楚。脂质运载蛋白2（Lcn2）是NASH病理过程中仅在肝脏和循环系统中产生的重要介质之一。
我们使用NASH小鼠模型，通过肝脑轴研究Lcn2作为NASH病理过程中神经炎症和神经退行性变的有效介质的作用。
结果显示，循环中高水平的Lcn2激活了大脑中的24p3R（脂质运载蛋白2受体），并优先诱导脑细胞释放高迁移率族蛋白B1（HMGB1）。释放的HMGB1作为Toll样受体4（TLR4）的优先配体，通过激活涉及NF-κB复合物活化p65蛋白的NOX-2信号传导诱导氧化应激。此外，HMGB1衍生的下游信号级联激活了NLRP3炎性小体，并促使脑细胞释放促炎细胞因子IL-6和IL-1β。此外，为了深化我们目前的认识，我们在原代脑内皮细胞中进行了体外研究，结果显示循环中高水平的Lcn2影响HMGB1的分泌。从机制上讲，我们还表明，NASH中Lcn2水平升高可能是诱导血脑屏障功能障碍的一个可能原因，因为这种脂肪因子降低了紧密连接蛋白Claudin 5的表达，并导致随后促炎细胞因子IL-6和IL-1β的升高。
总之，NASH诱导的脑部病变可能是由于Lcn2诱导的HMGB1释放增加以及随之而来的神经炎症所致。
