Specialized pro-resolving lipid mediator production in the cerebrospinal fluid is impaired in multiple sclerosis: implications for its pathogenesis and therapy
ECTRIMS Online Library. Kooij G. 09/13/19; 279540; 278
Gijs Kooij
Gijs Kooij
Contributions
Abstract

Abstract: 278

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Immunology

G. Kooij1, V. Chiurchiù2, P. Norris3, T. Olsson4, E. Iacobeus4, C. Teunissen1, B. Eggen5, B. Engelhardt6, H. de Vries1, C. Serhan3

1Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands, 2European Center for Brain Research, Santa Lucia Foundation, Rome, Italy, 3Harvard Medical School, Boston, MA, United States, 4Karolinska Institute, Stockholm, Sweden, 5Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Groningen, The Netherlands, 6Theodor Kocher Institute, Bern, Switzerland

Background and objective: The acute inflammatory response is host protective and efficient resolution of inflammation is required to prevent excessive inflammation and restore tissue homeostasis. This protective process is orchestrated by specialized pro-resolving lipid mediators (SPMs) that are biosynthesized from omega-3 fatty acids. In the chronic neuro-inflammatory disease multiple sclerosis (MS), the abundant presence of pro-inflammatory cells and wide-spread microglial activation within the central nervous system (CNS) suggests that this resolution process is impaired. Consequently, the uncontrolled inflammatory response will acquire a chronic nature, leading to severe tissue damage (neurodegeneration) and disease progression. To date, fundamental insights into the regulation of CNS-resolution processes and whether impairments in this system correlate with MS progression remain elusive.
Methods: We used liquid chromatography-tandem mass spectrometry (LC-MS-MS)-based metabololipidomics to reveal lipid mediator signatures in the cerebrospinal fluid (CSF) of RRMS (either in relapse or remission), SPMS and PPMS patients as well as age/sex matched controls.
Results: We identified unique lipid mediator signatures associated with MS clinical forms and provide first evidence for an altered resolution-inflammation pathway in MS. Specifically, we observed a reduction of SPMs like lipoxin B4 and resolvin D3 in various clinical disease stages along with high levels of classical eicosanoids. Epithelial cells from the choroid plexus were found to contribute to the production of SPMs and when isolated from post-mortem brain of MS patients to contain defects in SPM biosynthesis. SPM administration potently reduced the inflammatory profile of both human innate (microglia) and adaptive (Th1 and Th17) immune cells under inflammatory conditions and ameliorated clinical signs in MS mouse models.
Conclusion: By using metabololipidomic profiling of human CSF, we here provide critical evidence of a failed resolution pathway in MS, suggesting new insights into the pathogenesis and providing innovative diagnostic and therapeutic approaches for this neurodegenerative disease.
Disclosure: The authors declare that they have no conflict of interest. This study was financially supported by an IBRO Research Fellowship, the Nauta Fonds and VUmc MS Center Amsterdam, and the Dutch MS Research Foundation (14-878MS to GK).

Abstract: 278

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Immunology

G. Kooij1, V. Chiurchiù2, P. Norris3, T. Olsson4, E. Iacobeus4, C. Teunissen1, B. Eggen5, B. Engelhardt6, H. de Vries1, C. Serhan3

1Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands, 2European Center for Brain Research, Santa Lucia Foundation, Rome, Italy, 3Harvard Medical School, Boston, MA, United States, 4Karolinska Institute, Stockholm, Sweden, 5Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Groningen, The Netherlands, 6Theodor Kocher Institute, Bern, Switzerland

Background and objective: The acute inflammatory response is host protective and efficient resolution of inflammation is required to prevent excessive inflammation and restore tissue homeostasis. This protective process is orchestrated by specialized pro-resolving lipid mediators (SPMs) that are biosynthesized from omega-3 fatty acids. In the chronic neuro-inflammatory disease multiple sclerosis (MS), the abundant presence of pro-inflammatory cells and wide-spread microglial activation within the central nervous system (CNS) suggests that this resolution process is impaired. Consequently, the uncontrolled inflammatory response will acquire a chronic nature, leading to severe tissue damage (neurodegeneration) and disease progression. To date, fundamental insights into the regulation of CNS-resolution processes and whether impairments in this system correlate with MS progression remain elusive.
Methods: We used liquid chromatography-tandem mass spectrometry (LC-MS-MS)-based metabololipidomics to reveal lipid mediator signatures in the cerebrospinal fluid (CSF) of RRMS (either in relapse or remission), SPMS and PPMS patients as well as age/sex matched controls.
Results: We identified unique lipid mediator signatures associated with MS clinical forms and provide first evidence for an altered resolution-inflammation pathway in MS. Specifically, we observed a reduction of SPMs like lipoxin B4 and resolvin D3 in various clinical disease stages along with high levels of classical eicosanoids. Epithelial cells from the choroid plexus were found to contribute to the production of SPMs and when isolated from post-mortem brain of MS patients to contain defects in SPM biosynthesis. SPM administration potently reduced the inflammatory profile of both human innate (microglia) and adaptive (Th1 and Th17) immune cells under inflammatory conditions and ameliorated clinical signs in MS mouse models.
Conclusion: By using metabololipidomic profiling of human CSF, we here provide critical evidence of a failed resolution pathway in MS, suggesting new insights into the pathogenesis and providing innovative diagnostic and therapeutic approaches for this neurodegenerative disease.
Disclosure: The authors declare that they have no conflict of interest. This study was financially supported by an IBRO Research Fellowship, the Nauta Fonds and VUmc MS Center Amsterdam, and the Dutch MS Research Foundation (14-878MS to GK).

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