Abstract
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.
Highlights
In the periphery, immature dendritic cells (DCs) survey their environment and capture soluble antigens, like microbes and cell debris
Bone MarrowDerived DC (BMDC) were cultured with 200 μM monomethyl fumarate (MMF) either from the beginning or starting at the day of LPS stimulation to analyze if the time point of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation is crucial for its effect on DC maturation and surface marker expression
The expression of MHCII, CD80 and CD86 was reduced when BMDC were generated under Nrf2 activating conditions whereas addition of MMF on day 8 together with LPS, had almost no effect on activation marker expression (Figure 1B; Figure S1A in Supplementary Material)
Summary
Immature dendritic cells (DCs) survey their environment and capture soluble antigens, like microbes and cell debris Since they are barely immunogenic, immature DC express only low levels of major histocompatibility complex (MHC) II and costimulatory molecules but display marked phagocytic capacity which renders them critical for maintaining peripheral T cell tolerance [1, 2]. Nrf is involved in different aspects of cellular functions including differentiation, proliferation and inflammation by fostering antioxidative gene expression while suppressing the production of reactive oxygen species and proinflammatory cytokines as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling [13,14,15,16,17]. Systemic activation of Nrf mitigates autoimmune inflammation in scurfy mice [25]
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