Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130478 | GEO | 2019/07/31
REPOSITORIES: GEO
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Project description:Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential in redox balance, is a target of DMF, but the precise therapeutic mechanisms remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increased 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 and suggestively associated with increased ROS generation. 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.
2019-07-31 | GSE130491 | GEO
Project description:The fumarate ester dimethyl fumarate (DMF) has been introduced recently for the treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition resulting in neuronal demyelination and axonal loss. The complete mechanism of DMF action is unknown, but involves the depletion of intracellular glutathione and modification of thiols on Kelch-like ECH-associated protein 1 (Keap1), which in turn induces the expression of antioxidant response element genes. Previous work by our laboratory has shown that DMF reacts with a wide range of protein thiols in adipocytes, detected following ester hydrolysis by an antibody recognizing succinated proteins. We proposed that other intracellular thiol residues may also be irreversibly modified by DMF in neurons and astrocytes. DMF treatment of primary rodent neurons and astrocytes, as well as differentiated N1E-115 cells, resulted in the modification of 24 novel target proteins by mass spectrometry. Using this approach, we confirmed the identification and site of modification of the identified proteins, which include cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). An in vitro functional assay that measures the ability of cofilin-1 to sever the actin cytoskeleton demonstrated that DMF-modified cofilin-1 loses activity and generates less monomeric actin, potentially inhibiting cofilin’s cytoskeletal remodeling activity; an effect that could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. The oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, we demonstrate that in addition to the stimulation of the antioxidant response, DMF resulted in electrophilic modification of novel protein targets that provide new insight on the mechanisms supporting the neuroprotective and re-myelination benefits associated with DMF treatment.
2019-02-19 | PXD008314 | Pride
Project description:Cerebral aneurysms (CA) are a type of vascular disease that causes significant morbidity and mortality with rupture. Dysfunction of the vascular smooth muscle cells (VSMCs) from circle of Willis (CoW) vessels mediates CA formation as they are the major cell type of the arterial wall and play a role in maintaining vessel integrity. Dimethyl fumarate (DMF), a first-line oral treatment for relapsing-remitting multiple sclerosis, has been shown to inhibit VSMC proliferation and reduce CA formation in a mouse model. Potential unwanted side effects of DMF on VSMC function have not been investigated yet. The present study characterizes the impact of DMF on VSMC using scRNA-seq in CoW vessels following CA induction and further explores its role in mitochondrial function using in vitro VSMC cultures. Two weeks of DMF treatment following CA induction impaired the transcription of the glutathione redox system and downregulated mitochondrial respiration genes in VSMCs. In vitro, DMF treatment increased lactate formation and enhanced the mitochondrial production of reactive oxygen species (ROS). These effects rendered VSMCs vul-nerable to oxidative stress and led to mitochondrial dysfunction and enhancement of apoptosis. Taken together, our data support the concept that the DMF-mediated antiproliferative effect on VSMCs is linked to disturbed antioxidative functions resulting in altered mitochondrial metabo-lism. This negative impact of DMF treatment on VSMCs may be linked to preexisting alterations of cerebrovascular function due to renal hypertension. Therefore, before severe adverse effects emerge, it would be clinically relevant to develop indices or biomarkers linked to this disturbed antioxidative function to monitor patients undergoing DMF treatment.
2024-06-20 | GSE268079 | GEO
Project description:CD14+ monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to 'immunoparalysis.' Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets' vital role in human monocytes' pro-inflammatory responses. Natural low platelet counts in patients with immune thrombocytopenia (ITP) , platelet depletion in healthy human monocytes, or in vivo platelet depletion in mice, result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, supplementation with fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NF?B and MAPK p38. We pinpointed a vesicle-derived NF?B2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking MAPK p38a and NF?B p65 and NF?B2. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.
2024-08-14 | PXD052113 | Pride
Project description:Physiological stimuli such as thrombin, or pathological stimuli such as lysophosphatidic acid (LPA), activate platelets. The activated platelets bind to monocytes through P-selectin-PSGL-1 interactions, but also release the contents of their granules, commonly called “platelet releasate”. It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS is considered to be a potential regulator of protein function. In a previous study, we used THP-1 monocytic cells exposed to LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that are influenced by reversible cysteine oxidation. To gain a better understanding of the redox regulation of monocytes in atherosclerosis, we have now altered the modified biotin switch to selectively quantify protein sulfenic acid, a subpopulation of reversible cysteine oxidation. Using arsenite as reducing agent in the modified biotin switch assay, we were able to quantify 1161 proteins, in which more than 100 sulfenic acid sites were identified. Bioinformatics analysis of the quantified sulfenic acid sites highlighted the relevant, previously missed biological process of monocyte transendothelial migration, which included integrin β2. Flow cytometry validated the activation of LFA-1 (αLβ2) and Mac-1 (αMβ2), two subfamilies of integrin β2 complexes, on human primary monocytes following platelet releasate treatment. The activation of LFA-1 was mediated by ROS from NADPH oxidase (NOX) activation. Production of ROS and activation of LFA-1 in human primary monocytes were independent of P-selectin-PSGL-1 interaction. Our results proved the modified biotin switch assay to be a powerful tool with the ability to reveal new regulatory mechanisms and identify new therapeutic targets.
2016-10-10 | PXD004862 | Pride
Project description:IL-17-producing CD8+ (Tc17)T cells are implicated in the pathogenesis of multiple sclerosis (MS), thereby representing a promising target for therapy. We found that dimethyl fumarate (DMF), a first-line medication for MS upregulated reactive oxygen species (ROS) by glutathione depletion in murine Tc17 cells, which limited IL-17 and diverted Tc17 cells towards cytotoxic T lymphocyte (CTL) signature. DMF enhanced PI3K-AKT-FOXO1-T-bet- as well as STAT5-signaling leading to restricted permissive histone state at the Il17 locus. T-bet-deficiency, inhibiting PI3K-AKT, STAT5 or histone deacetylases prevented DMF-ROS-mediated IL-17 suppression. In MS patients with stable response, DMF suppressed IL-17 production by CD8+ T-cells and triggered diversion from Tc17 towards CTL signature along with enriched ROS-, PI3K-AKT-FOXO1-signaling, demonstrating comparable regulation across species. Accordingly, in the mouse model for MS, DMF limited Tc17-encephalitogenicity. Our findings disclose DMF-ROS-AKT-driven pathway, which selectively modulates Tc17 fate to ameliorate MS, thus opening avenue to develop markers and targets for specific therapy.
2018-07-11 | GSE116866 | GEO
Project description:IL-17-producing CD8+ (Tc17)T cells are implicated in the pathogenesis of multiple sclerosis (MS), thereby representing a promising target for therapy. We found that dimethyl fumarate (DMF), a first-line medication for MS upregulated reactive oxygen species (ROS) by glutathione depletion in murine Tc17 cells, which limited IL-17 and diverted Tc17 cells towards cytotoxic T lymphocyte (CTL) signature. DMF enhanced PI3K-AKT-FOXO1-T-bet- as well as STAT5-signaling leading to restricted permissive histone state at the Il17 locus. T-bet-deficiency, inhibiting PI3K-AKT, STAT5 or histone deacetylases prevented DMF-ROS-mediated IL-17 suppression. In MS patients with stable response, DMF suppressed IL-17 production by CD8+ T-cells and triggered diversion from Tc17 towards CTL signature along with enriched ROS-, PI3K-AKT-FOXO1-signaling, demonstrating comparable regulation across species. Accordingly, in the mouse model for MS, DMF limited Tc17-encephalitogenicity. Our findings disclose DMF-ROS-AKT-driven pathway, which selectively modulates Tc17 fate to ameliorate MS, thus opening avenue to develop markers and targets for specific therapy.
2018-07-11 | GSE116865 | GEO
Project description:Physiological stimuli such as thrombin or pathological stimuli such as lysophosphatidic acid (LPA) activate platelets. The activated platelets bind to monocyte through P-selectin-PSGL-1 interactions, but also release the contents of their granules, which were defined as platelet releasate. It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS has been viewed as a potential regulator of protein function. In previous study, we employed a model of THP-1 monocytic cells affected by LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that been influenced by reversible cysteine oxidation. To gain better understanding of the redox regulation of monocyte in atherosclerosis, we now extend the modified biotin switch to quantify protein sulfenic acid, a subpopulation of reversible cysteine oxidation. Using arsenite in the modified biotin-switch assay, we were able to quantify 1161 proteins, in which more than 100 sulfenic acid sites were identified. Bioinformatics analysis of the quantified sulfenic acid sites further highlighted biological processes of monocyte transendothelial migration including integrin β2. Flow cytometry validated the activation of LFA-1 (αLβ2) and Mac-1 (αMβ2), two subfamilies of integrin β2 complexes on human primary monocyte upon platelet releasate treatments. The activation of LFA-1 was mediated by ROS from NADPH oxidase (NOX) activation. Moreover, the production of ROS and the activation of LFA-1 in human primary monocyte induced by platelet releasate were independent of P-selectin-PSGL-1 interaction. The modified biotin switch assay proved to be a powerful tool with the ability to reveal new regulatory mechanisms and identify new therapeutic targets.
2016-10-10 | PXD003365 | Pride
Project description:Physiological stimuli such as thrombin or pathological stimuli such as lysophosphatidic acid (LPA) activate platelets. The activated platelets bind to monocyte through P-selectin-PSGL-1 interactions, but also release the contents of their granules, which were defined as platelet releasate. It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS has been viewed as a potential regulator of protein function. In previous study, we employed a model of THP-1 monocytic cells affected by LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that been influenced by reversible cysteine oxidation. To gain better understanding of the redox regulation of monocyte in atherosclerosis, we now extend the modified biotin switch to quantify protein sulfenic acid, a subpopulation of reversible cysteine oxidation. Using arsenite in the modified biotin-switch assay, we were able to quantify 1161 proteins, in which more than 100 sulfenic acid sites were identified. Bioinformatics analysis of the quantified sulfenic acid sites further highlighted biological processes of monocyte transendothelial migration including integrin β2. Flow cytometry validated the activation of LFA-1 (αLβ2) and Mac-1 (αMβ2), two subfamilies of integrin β2 complexes on human primary monocyte upon platelet releasate treatments. The activation of LFA-1 was mediated by ROS from NADPH oxidase (NOX) activation. Moreover, the production of ROS and the activation of LFA-1 in human primary monocyte induced by platelet releasate were independent of P-selectin-PSGL-1 interaction. The modified biotin switch assay proved to be a powerful tool with the ability to reveal new regulatory mechanisms and identify new therapeutic targets.
2016-10-10 | PXD003363 | Pride
Project description:Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a Drosophila Cdk5 model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses to pathology, or whether they are simply covariates of pathology that do not alter viability. We find, surprisingly, that increasing mitochondrial H2O2 correlates with improved survival. We also find evidence that drugs that alter the mitochondrial glutathione redox potential modulate survival primarily through the compensatory effects they induce rather than through their direct effects on the final mitochondrial glutathione redox potential per se. We also find that the response to treatment with a redox-altering drug varies dramatically depending on the age at which the drug is administered, the duration of the treatment, and the genotype of the individual receiving the drug. These data have important implications for the design and interpretation of studies investigating the effect of redox state on health and disease as well as on efforts to modify the redox state to achieve therapeutic goals.
2024-08-22 | GSE274587 | GEO