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Smoking increases the risk of developing rheumatoid arthritis (RA) and affects the severity of established RA. Smoking can impact on Th17 lymphocyte differentiation and function through activation of the aryl hydrocarbon receptor (AHR), a process with implications for the pathogenic mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective of this study was to establish any effect of smoking on the inflammatory tissue lesions of rheumatoid arthritis via the AHR and IL-17A.    Methods  Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established. Expression of  AHR ,  CYP1A1 ,  AHRR ,  IL6 ,  IL17A ,  IL17F ,  IL22 ,  IL23 ,  IL23R ,  IFNG ,  TBX21 ,  IDO1  and  FOXP3  genes were assessed in tissues and cultured cells using real-time PCR. Two-colour immunofluorescence was used to co-localise AHR and CYP1A1 protein in synovial tissues. The response of monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist, benzo( a )pyrene (B a P) was compared  in vitro .    Results   AHR  gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia. Expression was not influenced by smoking in either tissue. Evidence of AHR activation, indicated by  CYP1A1  and  AHRR  gene expression, was found only in synovia from patients who smoked. However,  IL17A  gene expression was lower in synovia from smokers.  TBX21  and  FOXP3  expression was not affected by smoking. Within the synovial tissues of smokers the principal cell type with evidence of AHR activation was a subset of synovial DCs. This observation was consistent with the sensitivity of human mo-DCs to B a P stimulation demonstrated  in vitro . Exposure to B a P affected mo-DC function as demonstrated by decreased  IL6  expression induced by PolyI:C, without affecting indoleamine 2,3 dioxygenase (IDO)1 expression.    Conclusion  Our findings show that one effect of smoking on inflamed rheumatoid synovial tissue involves activation of the AHR pathway. A subset of synovial DCs is important in the response to cigarette smoke. The potential for smoking to affect DC behaviour in joint tissues has relevance to both early and late phases of RA pathogenesis and warrants further investigation.

Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis