Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty ...acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
•Dietary fatty acids have profound influence on T cell differentiation in the gut•Middle- and long-chain fatty acids (LCFAs) support Th1 and Th17 cell differentiation•Short-chain fatty acids (SCFAs) lead to increased Treg cell differentiation•LCFAs worsen disease in an animal model of MS; SCFAs exert the opposite effect
Haghikia and colleagues show that dietary fatty acids (FAs) influence T cell differentiation in the gut, with short FAs leading to increased Treg cell differentiation and long FAs supporting Th1 and/or Th17 cell differentiation. These FAs differentially affect EAE severity, demonstrating a direct dietary impact on central nervous system autoimmunity.
The expression of selected microRNAs (miRNAs) known to be involved in the regulation of immune responses was analyzed in 74 patients with relapsing remitting multiple sclerosis (RRMS) and 32 healthy ...controls. Four miRNAs (miR-326, miR-155, miR-146a, miR-142-3p) were aberrantly expressed in peripheral blood mononuclear cells from RRMS patients compared to controls. Although expression of these selected miRNAs did not differ between treatment-naïve (n = 36) and interferon-beta treated RRMS patients (n = 18), expression of miR-146a and miR-142-3p was significantly lower in glatiramer acetate (GA) treated RRMS patients (n = 20) suggesting that GA, at least in part, restores the expression of deregulated miRNAs in MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (Tsub.H17) cells, which can ...also contribute to hypertension. Induction of Tsub.H17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating Tsub.H17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased Tsub.H17 cells and increased blood pressure. Our results connect high salt intake to the gutimmune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.
Inflammation in multiple sclerosis Haase, Stefanie; Linker, Ralf A.
Therapeutic Advances in Neurological Disorders,
2021, Letnik:
14
Book Review, Journal Article
Recenzirano
Odprti dostop
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterised pathologically by demyelination, gliosis, neuro-axonal damage and inflammation. ...Despite intense research, the underlying pathomechanisms driving inflammatory demyelination in MS still remain incompletely understood. It is thought to be caused by an autoimmune response towards CNS self-antigens in genetically susceptible individuals, assuming autoreactive T cells as disease-initiating immune cells. Yet, B cells were recognized as crucial immune cells in disease pathology, including antibody-dependent and independent effects. Moreover, myeloid cells are important contributors to MS pathology, and it is becoming increasingly evident that different cell types act in concert during MS immunopathology. This is supported by the finding that the beneficial effects of actual existing disease-modifying therapies cannot be attributed to one single immune cell-type, but rather involve immunological cooperation. The current strategy of MS therapies thus aims to shift the immune cell repertoire from a pro-inflammatory towards an anti-inflammatory phenotype, involving regulatory T and B cells and anti-inflammatory macrophages. Although no existing therapy actually exists that directly induces an enhanced regulatory immune cell pool, numerous studies identified potential net effects on these cell types. This review gives a conceptual overview on T cells, B cells and myeloid cells in the immunopathology of relapsing-remitting MS and discusses potential contributions of actual disease-modifying therapies on these immune cell phenotypes.
Summary
A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). ...Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T‐cells (Treg), contributing to immune suppression. Short‐chain fatty acids may induce Treg either by G‐protein‐coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T‐cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long‐chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on MS as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Recent studies revealed that modifying distinct intestinal bacterial populations may influence immune cell activation in the periphery, thus resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). While some bacteria and their antigenic products may protect against inflammation, others have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on multiple sclerosis as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Dimethyl fumarate is an orally available treatment option for relapsing–remitting multiple sclerosis (MS) in a new formulation with improved gastroenteric coating. The mode of action comprises ...immunomodulatory effects and an activation of nuclear (erythroid-derived 2) related factor mediated antioxidative response pathways leading to additional cytoprotective effects. In two pivotal phase III trials, dimethyl fumarate, 240 mg twice daily, reduced relapse rates by about 50 % as compared with placebo. In the DEFINE trial, progression of disability was also significantly reduced. Both trials demonstrated a significant reduction of gadolinium-enhanced lesions as well as T2 lesions on cranial MRI. The studies revealed a beneficial safety profile of dimethyl fumarate. The most prevalent side effects were transient flushing and gastrointestinal tract irritation. Dimethyl fumarate has recently been approved in the USA for the treatment of relapsing–remitting MS. The compound is a welcome addition to the immunomodulatory treatment armamentarium for MS patients and physicians alike.
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory ...effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood ...and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80-90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dimethyl fumarate (DMF) is one of the newer additions to the armamentarium of potent immunomodulators for the treatment of relapsing-remitting multiple sclerosis (RRMS). After more than 2 years of ...real-world experience and more than 190,000 patients currently treated with DMF worldwide, it is a good timepoint to review the experience gathered so far and to re-evaluate the potential of this first-line oral multiple sclerosis (MS) drug. Post-hoc analyses of clinical and magnetic resonance imaging (MRI) data, some comprising more than 6 years of drug exposure including patients from the clinical trials, and the overall notion in clinical practice widely confirm the good efficacy of DMF in RRMS. Despite an overall good safety profile, it became also clear that the necessary clinical vigilance while using DMF may not be neglected. So far, four reported cases of progressive multifocal leukoencephalopathy (PML), a towering shadow over many MS therapies, warrant proper attention in newly-updated risk management plans. This review recapitulates efficacy and safety aspects of DMF therapy in relation to reported data from the pivotal clinical trials. In addition, we summarize recent insights into DMF mechanisms of action drawn from the field of basic research which may have important implications for clinical practice.
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