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

Date Published: April 26, 2019

Publisher: Public Library of Science

Author(s): Alzahrani Abdullah, Mohammed Maged, Ibrahim Hairul-Islam M., Alwassil Osama I., Habash Maha, Alfuwaires Manal, Hanieh Hamza, Udai P. Singh.


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).

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.

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.

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.

Partial Text

Multiple sclerosis (MS) is the most common neurological autoimmune disease of the central nervous system (CNS). MS patients present variable patterns of relapsing remittance characterized by intermittent exacerbations. Such exacerbations and disease progression have often been reduced with disease-modifying therapies [1, 2]. However, some of these therapies exert negative side effects [3].

Despite the remarkable progress in understanding the genetic control of MS [30], limited evidence is available about the roles of environmental factors [4]. In this context, Ahr exemplifies a unique link between the immune system and environment by interacting with a variety of exogenous aromatic hydrocarbons. The accumulated evidence clearly demonstrates that the activation of Ahr by exogenous ligands attenuates inflammation in a murine model of MS [19–21]. Therefore, identifying new Ahr ligands is a promising treatment strategy to control proinflammatory mediators in MS patients. Herein, we identified GA as a novel Ahr agonist of natural origin using in silico, in vitro and in vivo approaches.




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