Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.
Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.
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作者：
Shiow LR;Favrais G;Schirmer L;Schang AL;Cipriani S;Andres C;Wright JN;Nobuta H;Fleiss B;Gressens P;Rowitch DH
炎症是新生儿白质损伤（NWMI）的主要危险因素，这与后期脑瘫的发展有关。尽管最近的研究表明 NWMI 中少突胶质细胞祖细胞 (OPC) 的成熟停滞，但对 OPC 具有直接影响的炎症介质的身份尚不清楚。在这里，我们研究了促炎性 IL-1β 诱导白质中环氧合酶 2 (COX2) 和前列腺素 E2 (PGE2) 产生的下游效应。首先，我们评估了受缺氧缺血性脑病影响的人类胎儿大脑和足月新生儿大脑中 COX2 的表达。在发育中的人脑中，COX2 在放射状胶质细胞、小胶质细胞和内皮细胞中表达。在伴有皮质下 WMI 的人类足月新生儿缺氧缺血性脑病病例中，COX2 在具有“A2”反应性的反应性星形胶质细胞中被强烈诱导。接下来，我们证明 OPCs 表达 PGE2 的 EP1 受体，并且 PGE2 直接作用于 OPCs 以阻止体外成熟。使用 EP1 特异性抑制剂（ONO-8711、SC-51089）进行药理学阻断，或 EP1 遗传缺陷会减弱 PGE2 的作用。在 IL-1β 诱导的 NWMI 模型中，星形胶质细胞也表现出“A2”反应性并诱导 COX2。此外，尼美舒利在体内抑制 COX2 可挽救髓鞘形成不足和行为障碍。这些发现表明，新生儿白质星形胶质细胞可以产生“A2”反应性，通过诱导 COX2-PGE2 信号传导（一种可针对新生儿神经保护的途径），有助于 NWMI 中 OPC 成熟停滞。
Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy. In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal hypoxic-ischemic encephalopathy cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with “A2” reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit “A2” reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop “A2” reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.
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影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
影响因子：
6.4
作者：
Billiards, Saraid S.;Haynes, Robin L.;Kinney, Hannah C.
通讯作者：
Kinney, Hannah C.
影响因子：
6.2
作者：
Back, Stephen A.;Rosenberg, Paul A.
通讯作者：
Rosenberg, Paul A.
影响因子：
6.1
作者：
Favrais, Geraldine;Schwendimann, Leslie;Lelievre, Vincent
通讯作者：
Lelievre, Vincent
DOI：
10.1523/jneurosci.2546-10.2010
发表时间：
2010-08-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chew LJ;Coley W;Cheng Y;Gallo V
通讯作者：
Gallo V