García-Bueno Borja, Serrats Jordi, Sawchenko Paul E
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and Clayton Medical Research Foundation, La Jolla, California 92037, USA.
J Neurosci. 2009 Oct 14;29(41):12970-81. doi: 10.1523/JNEUROSCI.2373-09.2009.
Systemic injection of lipopolysaccharide (LPS) is a widely used model of immune/inflammatory challenge, which can invoke a host of CNS responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis. Inducible vascular prostaglandin E(2) (PGE(2)) synthesis by endothelial (ECs) and/or perivascular cells (PVCs) (a macrophage-derived vascular cell type) is implicated in the engagement of HPA and other CNS responses, by virtue of their capacity to express cyclooxygenase-2 (COX-2) and microsomal PGE(2) synthase-1. Evidence from genetic and pharmacologic studies also supports a role for the constitutively expressed COX-1 in inflammation-induced activation of the HPA axis, although histochemical evidence to support relevant localization(s) and regulation of COX-1 expression is lacking. The present experiments fill this void in showing that COX-1 immunoreactivity (IR) and mRNA are detectable in identified PVCs and parenchymal microglia under basal conditions and is robustly expressed in these and ECs 1-3 h after intravenous injection of LPS (2 microg/kg). Confocal and electron microscopic analyses indicate distinct cellular/subcellular localizations of COX-1-IR in the three cell types. Interestingly, COX-1 expression is enhanced in ECs of brain PVC-depleted rats, supporting an anti-inflammatory role of the latter cell type. Functional involvement of COX-1 is indicated by the observation that central, but not systemic, pretreatment with the selective COX-1 inhibitor SC-560 attenuated the early phase of LPS-induced increases in adrenocorticotropin and corticosterone secretion. These findings support an involvement of COX-1 in bidirectional interplay between ECs and PVCs in initiating vascular PGE(2) and downstream HPA response to proinflammatory challenges.
全身注射脂多糖（LPS）是一种广泛应用的免疫/炎症刺激模型，它可引发一系列中枢神经系统反应，包括下丘脑-垂体-肾上腺（HPA）轴的激活。内皮细胞（ECs）和/或血管周围细胞（PVCs，一种巨噬细胞衍生的血管细胞类型）诱导性合成血管前列腺素E2（PGE2），由于它们具有表达环氧合酶-2（COX-2）和微粒体PGE2合酶-1的能力，因而参与了HPA轴及其他中枢神经系统反应。遗传和药理学研究的证据也支持组成型表达的COX-1在炎症诱导的HPA轴激活中发挥作用，尽管缺乏支持COX-1表达相关定位和调节的组织化学证据。本实验填补了这一空白，结果表明，在基础条件下，可在已识别的PVCs和实质小胶质细胞中检测到COX-1免疫反应性（IR）和mRNA，并且在静脉注射LPS（2微克/千克）后1-3小时，这些细胞以及ECs中COX-1均强烈表达。共聚焦显微镜和电子显微镜分析表明，COX-1-IR在这三种细胞类型中有不同的细胞/亚细胞定位。有趣的是，在脑PVC缺失大鼠的ECs中COX-1表达增强，这支持了后一种细胞类型的抗炎作用。选择性COX-1抑制剂SC-560进行中枢而非全身预处理可减弱LPS诱导的促肾上腺皮质激素和皮质酮分泌增加的早期阶段，这一观察结果表明了COX-1的功能参与。这些发现支持COX-1参与ECs和PVCs之间的双向相互作用，从而启动血管PGE2合成以及对促炎刺激的下游HPA反应。
