Stefanie Jörg

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.

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.

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.

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

Significance The alternative renin–angiotensin system pathway, the angiotensin (Ang)-(1–7)/Mas axis, may counterbalance Ang II-mediated proinflammatory effects. To investigate the role of the Ang-(1–7)/Mas axis in immune cell function and inflammatory diseases in vivo, we used two different chronic inflammatory animal models. Deletion of Mas affects macrophage function and phenotype independently of the underlying phagocyte stimulus and aggravates the clinical course of experimental autoimmune encephalomyelitis as well as atherosclerosis in mice by tipping the in vivo balance from M(IL-4+IL-13)- to M(LPS+IFNγ)-like macrophages. Thus, modulation of the Ang-(1–7)/Mas axis counteracts the proinflammatory role of Ang II by regulating the delicate equilibrium between M(LPS+IFNγ)- and M(IL-4+IL-13)-like macrophages, thereby representing a promising pharmacological target for chronic inflammatory diseases. 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.

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

Significance Multiple sclerosis (MS) is the most frequent neurological disease that leads to premature retirement in young adults. Progressive MS currently is not only incurable, but also untreatable. Here we show that the calcium channel antagonist nimodipine significantly attenuated clinical disease and central nervous system degeneration and also fostered remyelination in a mouse model of MS. The effect of nimodipine was microglia specific, inducing apoptosis and decreasing the production of neurotoxic molecules such as nitric oxide and reactive oxygen species both in vitro and in vivo. These results introduce a treatment option for MS and also may have broad therapeutic implications for chronic neuroinflammatory diseases in general. 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.

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

BackgroundIncreased 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.FindingsWe 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.ConclusionsOur findings indicate a functional role of α-synuclein in early EAE by increasing Th1 cell-mediated immune response.

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.