Mitchell K, Yang H-Y T, Berk J D, Tran J H, Iadarola M J
Neurobiology and Pain Therapeutics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Building 49, Room 1C20, 49 Convent Drive, MSC 4410, Bethesda, MD 20892-4410, USA.
Neuroscience. 2009 Jan 23;158(2):885-95. doi: 10.1016/j.neuroscience.2008.10.047. Epub 2008 Nov 7.
During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of cerebrospinal fluid (CSF) production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the small inducible cytokine A2 (SCYA2) gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCP-1 protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared with other rat CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the nuclear factor-kappa B (NF-kappaB) signaling cascade including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and inhibitor of kappa B alpha (IkappaBalpha) in choroid tissue. Given that we also detected increased levels of MCP-1 protein by ELISA, we sought to identify potential downstream targets of MCP-1 and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding endothelial leukocyte adhesion molecule 1 (E-selectin), a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during peripheral tissue inflammation, likely initiated by blood-borne inflammatory mediators, which may modify events in CNS.
在周围组织炎症期间，中枢神经系统（CNS）中的炎症过程可由血源性促炎介质引发。脉络丛是脑脊液（CSF）产生的部位，是血管系统与中枢神经系统之间高度特化的界面，因此，在周围组织炎症期间，该结构可能是血管腔与中枢神经系统之间通讯的重要元素。我们通过检测编码单核细胞趋化蛋白-1（MCP-1）的小诱导细胞因子A2（SCYA2）基因的表达，研究了脉络丛在周围组织炎症过程中的潜在参与情况。先前报道MCP-1蛋白在周围组织炎症期间在多种细胞中被诱导。在基础状态下，与其他大鼠中枢神经系统组织相比，SCYA2在脉络丛中高度表达。在后爪炎症期间，脉络丛中SCYA2表达显著升高，而在多种脑区中其表达保持不变。表达SCYA2的细胞与脉络丛密切相关，因为全身生理盐水冲洗导致血细胞血管耗竭并未显著改变脉络丛中SCYA2的表达。原位杂交表明，表达SCYA2的细胞定位于脉络丛基质。为了阐明SCYA2增加的潜在分子机制，我们检测了脉络丛组织中核因子-κB（NF-κB）信号级联中的基因，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和κBα抑制剂（IkappaBalpha）。鉴于我们还通过ELISA检测到MCP-1蛋白水平升高，我们试图鉴定MCP-1的潜在下游靶点，并观察到编码紧密连接蛋白TJP2和claudin 5的mRNA表达水平发生改变。最后，我们检测到编码内皮白细胞粘附分子1（E-选择素）的转录本显著上调，该分子可与MCP-1一起参与白细胞向脉络丛的募集。总之，这些结果表明，在周围组织炎症期间脉络丛发生了深刻变化，可能由血源性炎症介质引发，这可能会改变中枢神经系统中的事件。
