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Sulforaphane protects from T cell mediated autoimmune disease by inhibition of interleukin 23 and 12 in dendritic cells

ABSTRACT: Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with antiinflammatory properties. Even though the published reports are vague, most are best conceivable with an inhibition of T cell functions. We therefore analyzed the effect of SFN on T cell-mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis (EAE). Disease amelioration was associated with reduced interleukin (IL)-17 and IFN-gamma expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DC) inhibited TLR4-induced IL-12 and IL-23 production and the cytokine profile of T cells stimulated by SFN-treated DC. SFN suppressed TLR4-induced nuclear factor kappa B (NFκB) activity, without affecting the degradation of its inhibitor (IκB). Instead, SFN treatment of DC resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with NFκB p65 and inhibits its activity. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 promoter activity within the IL23a and IL12b promoter region. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS . Our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting p65-regulated IL-23 and IL-12 expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE54980 | GEO | 2014/02/13

SECONDARY ACCESSION(S): PRJNA238198

REPOSITORIES: GEO

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Project description:XCR1+ dendritic cells (DC) have been shown to excel in antigen cross-presentation for the activation of naÃ¯ve CD8 T cells. This property was reported to be associated to the subset of the XCR1+ DC expressing IL-12b upon ex vivo stimulation for 24 h with a mixture of CpG, IFN-Î³, and GM-CSF (Lin ML et al. Proc Natl Acad Sci USA. 2008. PMID: 18272486). DC found in the steady-state non-lymphoid tissues undergo an homeostatic, tolerogenic, maturation and migrate to the draining lymph nodes to interact with naive autoreactive T cells and induction their peripheral tolerance. In contrast, spleen DC are thought to exist solely in an immature state. The aim of this study was to re-examine heterogeneity within steady state spleen XCR1+ DC, in particular examining whether this population encompass a fraction of mature DCs as assessed through their expression of CCR7 and/or the Il12b gene. Indeed, we show that a small fraction of XCR1+ spleen DC constitutively mature into two distinct but likely successive activation stages characterized as CCR7+ and CCR7+Il12b+ respectively, and correlated with increasing ability to cross-present antigen to naÃ¯ve CD8 T cells. Transcriptomic analysis of the subsets of XCR1+ DC found in steady state spleen unexpectedly showed that their homeostatic maturation was unexpectedly associated with up-regulated of many genes thought to drive pro-inflammatory T-cell responses and previously found to be commonly induced upon maturation of distinct DC subsets in response to stimulation by various microbial-type stimuli (Vu Manh TP et al. Eur J Immunol. 2013. PMID: 23553052). Thus, our results reveal that spleen XCR1+ DC undergo constitutive maturation and emphasize the common mechanisms operating upon homeostatic, tolerogenic, DC maturation versus microbial-type stimuli-induced, immunogenic, DC maturation. DC were isolated from the spleen of untreated Il12b-EYFP reporter mice (Reinhardt RL et al. J Immunol. 2006. PMID:16849470) mice as previously described (Robbins SH et al. Genome Biol. 2008. PMID: 18218067; Baranek T et al. Cell Host Microbe. 2012. PMID: 23084923). DC subsets were sorted by flow cytometry according to the marker combinations described in the âcharacteristics: phenotypeâ field for each sample.

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Sulforaphane protects from T cell mediated autoimmune disease by inhibition of interleukin 23 and 12 in dendritic cells

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