Expression of Ccl11 associates with immune response modulation and protection against neuroinflammation in rats.
Expression of Ccl11 associates with immune response modulation and protection against neuroinflammation in rats.
复制标题
DOI：
10.1371/journal.pone.0039794
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jagodic M
中科院分区：
文献类型：
--
作者：
Adzemovic MZ;Öckinger J;Zeitelhofer M;Hochmeister S;Beyeen AD;Paulson A;Gillett A;Thessen Hedreul M;Covacu R;Lassmann H;Olsson T;Jagodic M
多发性硬化症（MS）是一种以中枢神经系统（CNS）炎症和脱髓鞘为特征的多基因疾病，其可以以实验性自身免疫性脑脊髓炎（EAE）为模型。大鼠10号染色体上的Eae 18 b基因座先前已与β-趋化因子表达的调节和EAE的严重程度相关。此外，人类中的同源趋化因子簇显示出与MS易感性相关的证据。我们在此建立了一个含有趋化因子簇的Eae 18 b基因座的同源大鼠品系（Ccl2，Ccl7，Ccl11，Ccl 12和Ccl 1），并利用髓鞘少突胶质细胞糖蛋白（MOG），诱导EAE，以表征遗传调控的潜在机制。与易感的DA品系相比，同类大鼠的疾病较轻，这反映在脱髓鞘减少和炎症细胞向大脑的募集减少。同源株EAE诱导后引流淋巴结和脊髓中Ccl 11 mRNA表达也显著增加。在淋巴结中，巨噬细胞是CCL 11的主要生产者，而巨噬细胞和淋巴细胞表达主要的CCL 11受体，即CCR 3。相应地，同源株也显示淋巴结中Ccr 3 mRNA表达显著增加。在CNS中，CCL 11的主要生产者是神经元，而CCR 3在神经元和产生CSF的室管膜细胞上检测到。这对应于同类大鼠脑脊液中CCL 11蛋白水平的增加。同类大鼠鞘内产生的CCL 11增加伴随着更紧密的血脑屏障，反映了更多的occludin+血管。此外，同源菌株显示出降低的抗原特异性应答和主要的抗炎Th 2表型。这些结果表明了神经炎症遗传调控的新机制。
Multiple sclerosis (MS) is a polygenic disease characterized by inflammation and demyelination in the central nervous system (CNS), which can be modeled in experimental autoimmune encephalomyelitis (EAE). The Eae18b locus on rat chromosome 10 has previously been linked to regulation of beta-chemokine expression and severity of EAE. Moreover, the homologous chemokine cluster in humans showed evidence of association with susceptibility to MS. We here established a congenic rat strain with Eae18b locus containing a chemokine cluster (Ccl2, Ccl7, Ccl11, Ccl12 and Ccl1) from the EAE- resistant PVG rat strain on the susceptible DA background and utilized myelin oligodendrocyte glycoprotein (MOG)-induced EAE to characterize the mechanisms underlying the genetic regulation. Congenic rats developed a milder disease compared to the susceptible DA strain, and this was reflected in decreased demyelination and in reduced recruitment of inflammatory cells to the brain. The congenic strain also showed significantly increased Ccl11 mRNA expression in draining lymph nodes and spinal cord after EAE induction. In the lymph nodes, macrophages were the main producers of CCL11, whereas macrophages and lymphocytes expressed the main CCL11 receptor, namely CCR3. Accordingly, the congenic strain also showed significantly increased Ccr3 mRNA expression in lymph nodes. In the CNS, the main producers of CCL11 were neurons, whereas CCR3 was detected on neurons and CSF producing ependymal cells. This corresponded to increased levels of CCL11 protein in the cerebrospinal fluid of the congenic rats. Increased intrathecal production of CCL11 in congenic rats was accompanied by a tighter blood brain barrier, reflected by more occludin+ blood vessels. In addition, the congenic strain showed a reduced antigen specific response and a predominant anti-inflammatory Th2 phenotype. These results indicate novel mechanisms in the genetic regulation of neuroinflammation.
登录
查看更多内容
影响因子：
4.8
作者：
Kitaura, M;Nakajima, T;Yoshie, O
通讯作者：
Yoshie, O
影响因子：
6
作者：
Bradl, M;Bauer, J;Lassmann, H
通讯作者：
Lassmann, H
影响因子：
5
作者：
Ockinger, J.;Stridh, P.;Olsson, T.
通讯作者：
Olsson, T.
影响因子：
--
作者：
Bugeja MJ;Booth D;Bennetts B;Heard R;Rubio J;Stewart G
通讯作者：
Stewart G
影响因子：
6.4
作者：
Storch, MK;Stefferl, A;Lassmann, H
通讯作者：
Lassmann, H