Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system
Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system
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DOI：
10.1016/j.bbi.2010.09.015
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发表时间：
2011-07-01
影响因子：
15.1
通讯作者：
Owens, T.
中科院分区：
文献类型：
--
作者：
Fuchtbauer, L.;Groth-Rasmussen, M.;Owens, T.
星形胶质细胞是血脑屏障胶质限制细胞的主要细胞成分，并通过趋化因子表达充当白细胞浸润的调节剂。我们研究了星形胶质细胞中的血管紧张素 II 受体 1 (AT1) 和相关的 NF-κ B 信号传导。血管紧张素II源自血管紧张素I被血管紧张素转化酶(ACE)裂解，血管紧张素I源自血管紧张素原经肾素裂解。在星形胶质细胞中表达显性失活 I kappa B α 的转基因小鼠（GFAP-I kappa B α-dn 小鼠）中，ACE 的表达水平略有增加，而也在 CNS 中组成型表达的血管紧张素原和肾素不受 NF-kappa B 抑制的影响。内嗅皮层传入穿通路径轴突单侧立体定向损伤后，白细胞浸润小鼠海马。通常响应于轴突横断后齿状回突触变性而发生的趋化因子CXCL10的上调在GFAP-I kappa B alpha-dn小鼠中被完全消除。病变后齿状回的小胶质细胞和星形胶质细胞中血管紧张素 II 上调，而 AT1 仅在星形胶质细胞上表达。用坎地沙坦阻断 AT1 导致损伤后 2 天海马中浸润巨噬细胞的数量显着增加。损伤引起的 T 细胞浸润增加和形态神经胶质反应不受影响，血脑屏障对辣根过氧化物酶保持完整。这些发现表明，血管紧张素 II 通过 All 向星形胶质细胞发出信号，在调节白细胞向中枢神经系统浸润以响应神经退行性刺激方面发挥着重要作用，并确定了针对中枢神经系统适应性免疫反应的治疗的潜在靶点。 (C) 2010 Elsevier Inc. 保留所有权利。
Astrocytes are the major cellular component of the blood-brain barrier glia limitans and act as regulators of leukocyte infiltration via chemokine expression. We have studied angiotensin-II receptor Type 1 (AT1) and related NF-kappa B signaling in astrocytes. Angiotensin II derives from cleavage of angiotensin I by angiotensin converting enzyme (ACE), angiotensin I deriving from angiotensinogen via cleavage by renin. Level of expression of ACE was slightly increased in transgenic mice that express dominant-negative I kappa B alpha in astrocytes (GFAP-I kappa B alpha-dn mice), whereas angiotensinogen and renin, also constitutively expressed in the CNS, were unaffected by NF-kappa B inhibition. Leukocytes infiltrate the hippocampus of mice after unilateral stereotactic lesion of afferent perforant path axons in the entorhinal cortex. Upregulation of the chemokine CXCL10 that normally occurs in response to synaptic degeneration in the dentate gyrus following axonal transection was totally abrogated in GFAP-I kappa B alpha-dn mice. Whereas angiotensin II was upregulated in microglia and astrocytes in the dentate gyrus post-lesion, AT1 was exclusively expressed on astrocytes. Blocking AT1 with Candesartan led to significant increase in numbers of infiltrating macrophages in the hippocampus 2 days post-lesion. Lesion-induced increases in T-cell infiltration and morphologic glial response were unaffected, and the blood-brain barrier remained intact to horseradish peroxidase. These findings show that angiotensin II signaling to astrocytes via All plays an important role in regulation of leukocyte infiltration to the CNS in response to a neurodegenerative stimulus, and identify potential targets for therapies directed at adaptive immune responses in the CNS. (C) 2010 Elsevier Inc. All rights reserved.