Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

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.

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis.

Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2+APC+ oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.

Role of the receptor Mas in macrophage-mediated inflammation in vivo.

Recently, an alternative renin-angiotensin system pathway has been described, which involves binding of angiotensin-(1-7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II-mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.

Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration.

The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.

Impact of combined sodium chloride and saturated long-chain fatty acid challenge on the differentiation of T helper cells in neuroinflammation.

BACKGROUND: There has been a marked increase in the incidence of autoimmune diseases like multiple sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Here, growing evidence suggests that ingredients of a Western diet like high intake of sodium chloride (NaCl) or saturated fatty acids may impact systemic immune responses, thus increasing disease susceptibility. Recently, we have shown that high dietary salt or long-chain fatty acid (LCFA) intake indeed aggravates T helper (Th) cell responses and neuroinflammation. METHODS: Naïve CD4+ T cells were treated with an excess of 40 mM NaCl and/or 250 µM lauric acid (LA) in vitro to analyze effects on Th cell differentiation, cytokine secretion, and gene expression. We employed ex vivo analyses of the model disease murine experimental autoimmune encephalomyelitis (EAE) to investigate whether salt and LCFA may affect disease severity and T cell activation in vivo. RESULTS: LCFA, like LA, together with NaCl enhance the differentiation of Th1 and Th17 cells as well as pro-inflammatory cytokine and gene expression in vitro. In cell culture, we observed an additive effect of LA and hypertonic extracellular NaCl (NaCl + LA) in Th17 differentiation assays as well as on IL-17, GM-CSF, and IL-2 gene expression. In contrast, NaCl + LA reduced Th2 frequencies. We employed EAE as a model of Th1/Th17 cell-mediated autoimmunity and show that the combination of a NaCl- and LA-rich diet aggravated the disease course and increased T cell infiltration into the central nervous system (CNS) to the same extent as dietary NaCl. CONCLUSIONS: Our findings demonstrate a partially additive effect of NaCl and LA on Th cell polarization in vitro and on Th cell responses in autoimmune neuroinflammation. These data may help to better understand the pathophysiology of autoimmune diseases such as MS.

Environmental factors in autoimmune diseases and their role in multiple sclerosis.

An increase in autoimmune diseases poses a socioeconomic challenge worldwide. Predisposing genetic risk has been identified, yet environmental factors make up a significant part of the risk in disease initiation and propagation. Next to improved hygiene and a gross reduction of infections, changes in dietary habits are one of the most evident Western lifestyle factors potentially associated with the increase in autoimmune diseases. Growing evidence suggests that particularly a typical 'Western diet', rich in saturated fat and salt and related pathologies can have a profound impact on local and systemic immune responses under physiologic and autoimmune conditions such as in multiple sclerosis (MS). In this review, we discuss recent findings on environmental factors influencing autoimmunity with an emphasis on the impact of 'Western diet' on immune homeostasis and gut microbiota in MS.

α-Synuclein deficiency promotes neuroinflammation by increasing Th1 cell-mediated immune responses.

BACKGROUND: Increased α-synuclein immunoreactivity has been associated with inflammatory activity in multiple sclerosis (MS) lesions, but the function of α-synuclein in neuroinflammation remains unknown. The aim of this study was to examine the role of α-synuclein in immunological processes in murine experimental autoimmune encephalomyelitis (EAE) as a model of MS. FINDINGS: We studied EAE in wildtype (aSyn(+/+)) and α-synuclein knockout (aSyn(-/-)) mice on a C57BL/6N background. In the spleen and spinal cord of aSyn(+/+) mice, we observed a gradual reduction of α-synuclein expression during EAE, starting already in the pre-symptomatic disease phase. Compared to aSyn(+/+) mice, aSyn(-/-) mice showed an earlier onset of symptoms but no differences in symptom severity at the peak of disease. Earlier symptom onset was accompanied by increased spinal cord infiltration of CD4(+) T cells, predominantly of interferon-γ-producing T helper 1 (Th1) cells, and reduced infiltration of regulatory T cells, whereas antigen-presenting cells were unaltered. Pre-symptomatically, aSyn(-/-) mice exhibited hyperproliferative CD4(+) splenocytes consistent with increased splenic interleukin-2 mRNA expression, resulting in increased numbers of Th1 cells in the spleen at the onset of symptoms. CONCLUSIONS: Our findings indicate a functional role of α-synuclein in early EAE by increasing Th1 cell-mediated immune response.

Pivotal role of choline metabolites in remyelination.

Neuroprotective approaches for central nervous system regeneration have not been successful in clinical practice so far and compounds that enhance remyelination are still not available for patients with multiple sclerosis. The objective of this study was to determine potential regenerative effects of the substance cytidine-5'-diphospho (CDP)-choline in two different murine animal models of multiple sclerosis. The effects of exogenously applied CDP-choline were tested in murine myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. In addition, the cuprizone-induced mouse model of de- and remyelination was used to specifically test the hypothesis that CDP-choline directly increases remyelination. We found that CDP-choline ameliorated the disease course of experimental autoimmune encephalomyelitis and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, CDP-choline effectively enhanced myelin regeneration and reversed motor coordination deficits. The increased remyelination arose from an increase in the numbers of proliferating oligodendrocyte precursor cells and oligodendrocytes. Further in vitro studies suggest that this process is regulated by protein kinase C. We thus identified a new mechanism to enhance central nervous system remyelination via the choline pathway. Due to its regenerative action combined with an excellent safety profile, CDP-choline could become a promising substance for patients with multiple sclerosis as an add-on therapy.

Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells.

To date, the intracellular signaling pathways involved in dendritic cell (DC) function are poorly understood. The antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been shown to affect maturation, function, and subsequent DC-mediated T cell responses of murine and human DCs. In experimental autoimmune encephalomyelitis (EAE), as prototype animal model for a T helper cell-mediated autoimmune disease, antigen presentation, cytokine production, and costimulation by DCs play a major role. We explore the role of Nrf2 in DC function, and DC-mediated T cell responses during T cell-mediated autoimmunity of the central nervous system using genetic ablation and pharmacological activation in mice and men to corroborate our data in a translational setting. In murine and human DCs, monomethyl fumarate induced Nrf2 signaling inhibits DC maturation and DC-mediated T cell proliferation by reducing inflammatory cytokine production and expression of costimulatory molecules. In contrast, Nrf2-deficient DCs generate more activated T helper cells (Th1/Th17) but fewer regulatory T cells and foster T cell proliferation. Transfer of DCs with Nrf2 activation during active EAE reduces disease severity and T cell infiltration. Our data demonstrate that Nrf2 signaling modulates autoimmunity in murine and human systems via inhibiting DC maturation and function thus shedding further light on the mechanism of action of antioxidative stress pathways in antigen-presenting cells.

High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells.

Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiation. During the initiation phase of MOG35-55 EAE, we did not observe altered DC frequencies or co-stimulatory capacities in lymphoid organs, while IL-17A production and Th17 cells in the spleen were significantly increased. Complementary ex vivo analyses of the spinal cord during the effector phase of EAE showed increased frequencies of Th17 cells, but did not reveal differences in phenotypes of CNS invading DCs. Finally, adaption of transgenic mice harboring a MOG specific T cell receptor to a high-salt diet led to aggravated clinical disease only after active immunization. Wild-type mice adapted to a high-salt diet in the effector phase of EAE, bypassing the priming phase of T cells, only displayed mildly aggravated disease. In summary, our data argue for a direct effect of NaCl on Th17 cells in neuroinflammation rather than an effect primarily exerted via DCs. These data may further fuel our understanding on the dietary impact on different immune cell subsets in autoimmune diseases, such as multiple sclerosis.