Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis

Abstract

Background Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE). Methods An in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4 + T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG) 35-55 and the adoptive transfer of encephalitogenic CD4 + T cells were used to induce EAE. Results Molecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 ( Cyp1a1 ) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo , GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4 + CD45 + T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4 + T cells were not entirely responsible for the ameliorative effects of GA. Conclusion Our findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS.

Epigenetic Regulations of AhR in the Aspect of Immunomodulation

“…Another class of AhR ligands is composed of tryptophan-based molecules that can be derived from the diet or endogenously produced by the host organism [ 90 ] such as 6-formylindolo[3,2-b]carbazole (FICZ), indolo-[3,2-b]-carbazole (ICZ, converted from indole-3-carbinal which is found at especially high levels in cruciferous vegetables [ 91 ]) or kynurenine [ 77 ], cinnabarinic acid [ 92 ], galic acid (3,4,5-trihydroxybenzoic acid–metabolite of shikimate pathway) [ 93 ]. Generally, FICZ is an ultraviolet photoproduct of L-tryptophan, but it can also be generated during other metabolic pathways such as tryptamine deamination or tryptophan oxidation by intracellular oxidants [ 78 , 91 ].…”

Prediction of nanographene binding-scores to trout cellular receptors and cytochromes

“…Any induced tCYP1A and/or tCYP3A enzyme activities can also be monitored using ethoxyresorufin-O-deethylas(EROD) or benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylase (BFCOD) activity assays, respectively. To estimate possible induced immunological responses and/or to explain differences among AHR modulations observed across species 46 , concentration-dependent effects on trout immunosuppression 25 , inflammation (downregulation of il6, crp , or upregulation of tgfb ) and/or T cell and macrophage activation 47 , may also be performed. Combining the information generated by in silico screening with future in vitro and in vivo experimentation, forms an integrative approach for unrevealling the bio-interactions and effects induced by nGs/nGOs and expanding our knowledge of these highly bio-interactive planar hydrophobic substances.…”

Pinocembrin attenuates benzo(a)pyrene‐induced CYP1A1 expression through multiple pathways: An in vitro and in vivo study

“…The normalization with endogenous GAPDH provided the relative gene expression for the assessment of the various threshold cycles between the treated and untreated cells via the 2DDCt technique. [ 5 ]…”

“…[ 2,3 ] Benzo( a )pyrene diol epoxide (BPDE), which is a metabolite of B(a)P, can develop DNA adducts, causing DNA mutations and initiating tumorigenesis. [ 4 ] A ligand‐activated transcription factor known as aryl hydrocarbon receptor [ 5 ] is maintained in the cytoplasm by complexing with c‐Src kinase and some other cytosolic components. Upon activation, AhR is released from the complex, translocates to the nucleus, and develops an ARNT heterodimer.…”