Abstract
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.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), causing loss of sensory and motor functions in affected individuals
The congenic strain developed an overall milder disease with lower mean EAE score from day 14 post immunization (p.i.) until the end of the experiment compared to the Dark Agouti (DA) strain (Figure 1A)
In order to study the kinetics of the expression of the chemokine genes during the induction of disease, mRNA levels of Ccl2, Ccl7, Ccl11, Ccl12 and Ccl1 were measured in lymph nodes and spinal cords from parental DA and Piebald Virol Glaxo (PVG).av1 rats, at day 0, 5, 7 and 12 days after Myelin oligodendrocyte glycoprotein (MOG) immunization, using real-time quantitative PCR
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), causing loss of sensory and motor functions in affected individuals. The disease is polygenic, and several genes contributing to susceptibility have been identified and confirmed [1,2]. Characterization of the molecular mechanisms that mediate influence of MS risk genes can provide novel insights into disease pathogenesis. The genes identified so far still explain only a part of the disease heritability [4]. The underlying mechanisms are described only for a limited set of genes. To further dissect the genetic and pathological mechanisms of neuroinflammation, several animal models are used. Myelin oligodendrocyte glycoprotein (MOG)induced experimental autoimmune encephalomyelitis (EAE) is a well characterized animal model of MS, sharing several important features including T helper 1 (Th1), Th17 and B-cell involvement as well as histopathological characteristics [5,6,7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
