The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis
Abstract Background Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute p...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-09-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0969-4 |
| _version_ | 1811278272806256640 |
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| author | Silvy Mardiguian Emma Ladds Roberta Turner Hazel Shepherd Sandra J. Campbell Daniel C. Anthony |
| author_facet | Silvy Mardiguian Emma Ladds Roberta Turner Hazel Shepherd Sandra J. Campbell Daniel C. Anthony |
| author_sort | Silvy Mardiguian |
| collection | DOAJ |
| description | Abstract Background Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS. Methods Mice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed. Results Compared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions. Conclusions The APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse. |
| first_indexed | 2024-04-13T00:31:47Z |
| format | Article |
| id | doaj.art-f915dc467ff34f2599d9a13de3572eb4 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T00:31:47Z |
| publishDate | 2017-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-f915dc467ff34f2599d9a13de3572eb42022-12-22T03:10:27ZengBMCJournal of Neuroinflammation1742-20942017-09-0114111210.1186/s12974-017-0969-4The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosisSilvy Mardiguian0Emma Ladds1Roberta Turner2Hazel Shepherd3Sandra J. Campbell4Daniel C. Anthony5Department of Pharmacology, University of OxfordDepartment of Pharmacology, University of OxfordDepartment of Pharmacology, University of OxfordDepartment of Pharmacology, University of OxfordDepartment of Pharmacology, University of OxfordDepartment of Pharmacology, University of OxfordAbstract Background Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS. Methods Mice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed. Results Compared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions. Conclusions The APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.http://link.springer.com/article/10.1186/s12974-017-0969-4Multiple sclerosisLipopolysaccharideAcute phase responseVCAM-MPIO |
| spellingShingle | Silvy Mardiguian Emma Ladds Roberta Turner Hazel Shepherd Sandra J. Campbell Daniel C. Anthony The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis Journal of Neuroinflammation Multiple sclerosis Lipopolysaccharide Acute phase response VCAM-MPIO |
| title | The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| title_full | The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| title_fullStr | The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| title_full_unstemmed | The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| title_short | The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| title_sort | contribution of the acute phase response to the pathogenesis of relapse in chronic relapsing experimental autoimmune encephalitis models of multiple sclerosis |
| topic | Multiple sclerosis Lipopolysaccharide Acute phase response VCAM-MPIO |
| url | http://link.springer.com/article/10.1186/s12974-017-0969-4 |
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