| 1. |
- Berglund, Rasmus, et al.
(author)
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Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation
- 2020
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In: Science Immunology. - Stockholm : Karolinska Institutet, Dept of Clinical Neuroscience. - 2470-9468.
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.
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| 2. |
- Carlström, Karl E., et al.
(author)
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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
- 2019
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1, s. 1-13
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Journal article (peer-reviewed)abstract
- Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.
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| 3. |
- Ewing, Ewoud
(author)
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The role of epigenetics in multiple sclerosis development, progression and treatment
- 2020
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Doctoral thesis (other academic/artistic)abstract
- The overall aim of this thesis was to determine epigenetic changes in peripheral immune cells from Multiple Sclerosis (MS) patients. MS is a chronic inflammatory neurodegenerative disease, which initially presents itself during young adulthood. Big consortia have identified over 230 different polymorphisms contributing to the risk of developing disease, with many of these polymorphisms located in immune genes. However, the odds ratios of these polymorphisms are small and many known environmental risk factors are contributing to the disease. This indicates that the risk may partially be conferred through epigenetic changes such as DNA methylation. In this thesis, we investigate the role of DNA methylation in different peripheral immune cells using genome-wide DNA methylation arrays. We first characterized DNA methylation patterns in four different immune cell types form relapsing-remitting (RRMS), secondary-progressive (SPMS) patients and healthy controls (HC) and compared them with each other. Here we found a shared signature between all cells types, and in SPMS we found a specific neurodegenerative signal, while in MS patients, we saw lymphocyte signaling and T cell activation being affected. The top changes in CD4+ T cells indicate a change in the VMP1/MIR21 locus. We functionally investigated this and found lower miR-21 expression and an increase of miR-21 target genes. Because the most numerous methylation changes were found in CD19+ B cells, we further investigated CD19+ cells in a second larger cohort. After meta-analysis, the changes in B cells indicate differences in metabolism and activation between RRMS and HC. To analyze the shared pathway data, we developed a method to cluster pathways, which we further developed into an R package called GeneSetCluster. We investigated the effects of dimethyl fumarate (DMF) and rituximab treatment on DNA methylation in CD4+ and CD14+ cells. The different treatments had a different cell type specific signature as well as different kinetics. After DMF treatment, we found changes in reactive oxygen species (ROS) signaling and T cell subtype associated genes. Furthermore, we identified a polymorphism associated with treatment outcome and ROS production that does not associate with disease susceptibility. After rituximab treatment, we found differences in activation, metabolism and motility associated genes. Our findings collectively underline the importance of investigating epigenetic changes in multiple cell types to identify novel, potentially modifiable,
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| 4. |
- Lund, Harald, et al.
(author)
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Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.
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