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Journal of Immunology (Baltimore, Md. :... Sep 2023Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of...
Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of the endogenous metabolite itaconate, which is abundantly produced by LPS-activated macrophages, has recently been identified as a potent anti-inflammatory agent. The anti-inflammatory effects of 4-OI share a significant overlap with those of dimethyl fumarate (DMF), a derivate of another Krebs cycle metabolite fumarate, which is already in use clinically for the treatment of inflammatory diseases. In this study we show that both 4-OI and DMF induce secretion of the 33-kDa form of annexin A1 from murine bone marrow-derived macrophages, an effect that is much more pronounced in LPS-stimulated cells. We also show that this 4-OI- and DMF-driven annexin A1 secretion is NRF2-dependent and that other means of activating NRF2 give rise to the same response. Lastly, we demonstrate that the cholesterol transporter ABCA1, which has previously been implicated in annexin A1 secretion, is required for this process in macrophages. Our findings contribute to the growing body of knowledge on the anti-inflammatory effects of the Krebs cycle metabolite derivatives 4-OI and DMF.
Topics: Mice; Animals; Dimethyl Fumarate; NF-E2-Related Factor 2; Annexin A1; Lipopolysaccharides; Anti-Inflammatory Agents
PubMed: 37578391
DOI: 10.4049/jimmunol.2200848 -
Frontiers in Immunology 2023Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity...
BACKGROUND AND OBJECTIVE
Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response.
MATERIAL AND METHODS
PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively.
RESULTS
In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes).
CONCLUSIONS
Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
Topics: Humans; Dimethyl Fumarate; Multiple Sclerosis; Immunosuppressive Agents; Leukocytes, Mononuclear; Killer Cells, Natural; Biomarkers
PubMed: 37483622
DOI: 10.3389/fimmu.2023.1209923 -
Pharmaceuticals (Basel, Switzerland) Oct 2020Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised... (Review)
Review
Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated.
PubMed: 33066228
DOI: 10.3390/ph13100306 -
Journal Der Deutschen Dermatologischen... Nov 2022
Topics: Humans; Dimethyl Fumarate; Hyperpigmentation
PubMed: 36354064
DOI: 10.1111/ddg.14889 -
Blood Aug 2023Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major...
Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of patients with CTCL, creating an urgent need for new and effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and, thus, represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and, specifically, kill CTCL cells. To translate these findings to applications in a clinical setting, we performed a multicentric phase 2 study evaluating oral DMF therapy in 25 patients with CTCL stages Ib to IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). End points were safety and efficacy. We evaluated skin involvement (using a modified severity weighted assessment tool [mSWAT]), pruritus, quality of life, and blood involvement, if applicable, as well as translational data. Upon skin analysis, 7 of 23 (30.4%) patients showed a response with >50% reduction in the mSWAT score. Patients with high tumor burden in the skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB-inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable, with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase 3 study or real-life patient care as well as in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT02546440.
Topics: Humans; Dimethyl Fumarate; NF-kappa B; Quality of Life; Skin Neoplasms; Neoplasm Recurrence, Local; Lymphoma, T-Cell, Cutaneous; Pruritus
PubMed: 37217183
DOI: 10.1182/blood.2022018669 -
Multiple Sclerosis (Houndmills,... Oct 2019
Topics: Dimethyl Fumarate; Humans; Immunosenescence; Leukoencephalopathy, Progressive Multifocal; Lymphopenia
PubMed: 31208273
DOI: 10.1177/1352458519858603 -
Medicinal Research Reviews Sep 2019Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to... (Review)
Review
Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS-mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.
Topics: Animals; Dermatologic Agents; Dimethyl Fumarate; Humans
PubMed: 30756407
DOI: 10.1002/med.21567 -
Gut Microbes 2023Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the...
Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the underlying mechanisms whereby neutrophils regulate IELs to inhibit intestinal inflammation are still not completely understood. Here, we found that depletion of neutrophils (especially CD177 subset) caused expansion of colitogenic TCRγδCD8αα IELs, increased intestinal inflammation, and dysbiosis after dextran sulfate sodium exposure or infection in mice. scRNA-seq analysis revealed a pyroptosis-related gene signature and hyperresponsiveness to microbiota in TCRγδCD8αα IELs from colitic mice. Microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), as well as fumarate-producing microbiotas, decreased in the feces of colitic mice. Elimination of dysbiosis by antibiotics treatment or co-housing procedure and DMF supplementation restrained TCRγδCD8αα IEL activation. Consistently, DMF significantly alleviated intestinal mucosal inflammation in mice through restricting gasdermin D (GSDMD)-induced pyroptosis of TCRγδCD8αα IELs. Therefore, our data reveal that neutrophils inhibit intestinal inflammation by promoting microbiota-derived DMF to regulate TCRγδCD8αα IEL activation in a GSDMD-mediated pyroptosis-dependent manner, and that DMF may serve as a therapeutic target for the management of intestinal inflammation.
Topics: Mice; Animals; Dimethyl Fumarate; Intraepithelial Lymphocytes; Mice, Knockout; Dysbiosis; Neutrophils; Gastrointestinal Microbiome; Intestinal Mucosa; Inflammation; Mice, Inbred C57BL
PubMed: 36729914
DOI: 10.1080/19490976.2023.2172668 -
Drugs Dec 2019Dimethyl fumarate (Tecfidera) is approved for the treatment of relapsing forms of multiple sclerosis (MS). Based on evidence from the clinical trial and real-world... (Review)
Review
Dimethyl fumarate (Tecfidera) is approved for the treatment of relapsing forms of multiple sclerosis (MS). Based on evidence from the clinical trial and real-world settings, dimethyl fumarate is an effective treatment in this patient population, with benefits maintained over the longer term. In the pivotal, placebo-controlled phase III DEFINE and CONFIRM trials in adults with relapsing-remitting multiple sclerosis (RRMS), twice-daily dimethyl fumarate reduced clinical relapse and MRI measures of disease activity and improved some aspects of health-related quality of life (HR-QoL). Reduced disability progression was also observed with dimethyl fumarate in DEFINE. Results in predominantly East Asian patients (APEX trial) were reflective of those seen in DEFINE and CONFIRM. Dimethyl fumarate had an acceptable tolerability profile. The most common adverse events were flushing and gastrointestinal events, which were of mild or moderate severity and appear to be largely manageable. Thus twice-daily dimethyl fumarate remains an effective treatment option for use in patients with RRMS, with the convenience of oral administration.
Topics: Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting
PubMed: 31784875
DOI: 10.1007/s40265-019-01229-3 -
Annals of Clinical and Translational... Oct 2021Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS.
METHODS
Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life.
RESULTS
A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (-1.12 [-3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [-0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups.
INTERPRETATION
Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Dimethyl Fumarate; Double-Blind Method; Female; Humans; Immunologic Factors; Male; Middle Aged; Outcome Assessment, Health Care
PubMed: 34477330
DOI: 10.1002/acn3.51446