Understanding the Role of Aryl Hydrocarbon Receptor in RA Pathogenesis

Understanding the Role of Aryl Hydrocarbon Receptor in RA Pathogenesis

A new review entitled “Aryl hydrocarbon receptor antagonism and its role in rheumatoid arthritis” published in the Journal of Experimental Pharmacology highlights the current knowledge about the role of aryl hydrocarbon receptor (Ahr), also known as dioxin receptor, in immune cells during rheumatoid arthritis pathogenesis, suggesting its use as a potential target.

In rheumatoid arthritis (RA) patients’ bone damage and cartilage loss are triggered by osteoclasts — cells that degrade bone to initiate normal bone remodeling and resorption — and fibroblast-like synoviocytes (FLS), which are structures located inside joints in the synovium and implicated in the pathogenesis of chronic inflammatory diseases. The immune system, particularly T-cells, dendritic cells, macrophages, and B-cells as well as pro-inflammatory cytokines such as IL-6 and TNF-α, have been implicated in RA pathogenesis. Neutralizing antibodies against IL-6 and TNF-α has been suggested as a promising therapy against RA. However the pathogenic mechanisms of RA are still poorly understood.

Interactions between environmental and genetic risk factors, such as smoking, infection and the recognized HLA-DRB1 alleles that encode a shared epitope (SE), have been shown to induce RA development. Researchers have previously shown that Ahr present in helper T-cells contribute to the development of collagen-induced arthritis in a mouse model of RA. In addition, other studies have shown that cigarette smoke condensate, which contains several ligands of Ahr, as well as pure Ahr ligands intensify RA by changing bone metabo­lism and inducing pro-inflammatory responses in FLS. Accordingly, several Ahr antagonists such as α-naphthoflavone, resveratrol, and GNF351 have been shown to reverse the effect of Ahr ligands in RA pathogenesis. Several research teams have reported an association between SE and cigarette smoking, which contains Ahr ligands such as 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), 3-methyl cholanthrene (3-MC), and benzo[a]pyrene (BaP) and RA susceptibility.  However the exact mechanisms by which Ahr ligands contribute to RA development are still not well understood.

In this review, the authors note that dioxin-exposed patients often suffer from several different types of inflammatory diseases, including rheumatoid disorders. Additionally, expression of Ahr, CYP1A1, and inflammatory cytokines, including IL-1β and IL-6, has been found in high levels in peripheral blood of such patients, and the authors now hope to characterize new potential Ahr antagonists with strong anti-inflammatory properties to improve the signs and symptoms of RA in dioxin-exposed patients.

Although there has been significant advances in understanding the role of Ahr in RA pathogenesis, more studies are needed to reveal the precise molecular mechanisms by which Ahr deficiency or Ahr antagonists inhibit CIA development in mice models of the disease and attenuate the disease phenotype in cells isolated from RA patients.

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