Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats.
Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats.
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DOI：
10.1016/j.bbi.2018.02.015
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Zhang Y;Xu N;Ding Y;Zhang Y;Li Q;Flores J;Haghighiabyaneh M;Doycheva D;Tang J;Zhang JH
趋化素（Chemerin）是一种脂肪因子，据报道它可减少促炎细胞因子的产生和中性粒细胞浸润。本研究探讨了趋化素及其天然受体ChemR23，以及其下游介质钙调蛋白依赖性蛋白激酶激酶2（CAMKK2）/腺苷酸活化蛋白激酶（AMPK）/核因子红细胞2相关因子2（Nrf2）在新生大鼠生发基质出血（GMH）后的作用，特别关注炎症方面。在出生后第7天的幼鼠中，通过脑实质内注射细菌胶原酶（0.3U）诱导GMH。结果表明，人重组趋化素（rh - Chemerin）改善了GMH后的神经和形态学结果。rh - Chemerin在72小时促进了脑室周围区域M2型小胶质细胞的聚集和增殖。rh - Chemerin增加了CAMKK2、AMPK的磷酸化以及Nrf2的表达，并降低了白细胞介素 - 1β（IL - 1β）、白细胞介素 - 6（IL - 6）和肿瘤坏死因子 - α（TNF - α）的水平。通过脑室内给予脂质体包裹的特异性ChemR23（Lipo - alpha - NETA）、CAMKK2（Lipo - STO - 609）和AMPK（Lipo - Dorsomorphin）抑制剂，选择性抑制小胶质细胞中的ChemR23/CAMKK2/AMPK信号通路，增加了IL - 1β、IL - 6和TNF - α的表达水平，表明小胶质细胞中的ChemR23/CAMKK2/AMPK信号通路在GMH后抑制了炎症反应。总之，这些数据表明rh - Chemerin通过促进ChemR23/CAMKK2/AMPK/Nrf2通路改善了GMH诱导的炎症反应，并且M2型小胶质细胞可能是这种作用的主要介质。因此，rh - Chemerin可作为一种潜在的药物来减轻GMH后的炎症反应。
Chemerin, an adipokine, has been reported to reduce the production of pro-inflammatory cytokines and neutrophil infiltration. This study investigated the role of Chemerin and its natural receptor, ChemR23, as well as its downstream mediator calmodulin-dependent protein kinase kinase 2 (CAMKK2)/adenosine monophosphate-activated protein kinase (AMPK)/Nuclear factor erythroid 2-related factor 2 (Nrf2) following germinal matrix hemorrhage (GMH) in neonatal rats, with a specific focus on inflammation. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. The results demonstrated that human recombinant Chemerin (rh-Chemerin) improved neurological and morphological outcomes after GMH. Rh-Chemerin promoted accumulation and proliferation of M2 microglia in periventricular regions at 72 hours. Rh-Chemerin increased phosphorylation of CAMKK2, AMPK and expression of Nrf2, and decreased IL-1beta, IL-6 and TNF-alpha levels. Selective inhibition of ChemR23/CAMKK2/AMPK signaling in microglia via intracerebroventricular delivery of liposome-encapsulated specific ChemR23 (Lipo-alpha-NETA), CAMKK2 (Lipo-STO-609) and AMPK (Lipo-Dorsomorphin) inhibitor increased the expression levels of IL-1beta, IL-6 and TNF-alpha, demonstrating that ChemR23/CAMKK2/AMPK signaling in microglia suppressed inflammatory response after GMH. Cumulatively, these data showed that rh-Chemerin ameliorated GMH-induced inflammatory response by promoting ChemR23/CAMKK2/AMPK/Nrf2 pathway, and M2 microglia may be a major mediator of this effect. Thus, rh-Chemerin can serve as a potential agent to reduce the inflammatory response following GMH.
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