Donate Paula B, Alves de Lima Kalil, Peres Raphael S, Almeida Fausto, Fukada Sandra Y, Silva Tarcilia A, Nascimento Daniele C, Cecilio Nerry T, Talbot Jhimmy, Oliveira Rene D, Passos Geraldo A, Alves-Filho José Carlos, Cunha Thiago M, Louzada-Junior Paulo, Liew Foo Y, Cunha Fernando Q
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, CEP 14049-900, Brazil.
Departament of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, CEP 14049-900, Brazil.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2017120118. Epub 2020 Dec 21.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
类风湿性关节炎（RA）是一种以关节破坏和严重病残为特征的慢性炎症性疾病。吸烟（CS）会加剧RA的发病率和严重程度。尽管Th17细胞和芳烃受体（AhR）与之有关联，但CS诱导RA发展的机制仍不清楚。在此，我们通过转录组分析表明，在存在AhR激动剂或富含CS的培养基的情况下， 在Th17细胞中被特异性诱导。如此诱导产生的 被包装到Th17产生的细胞外囊泡中，并作为一种促炎介质，通过下调COX2增加破骨细胞生成。在体内，在小鼠关节炎模型中对 进行关节敲低可减少关节中破骨细胞的数量。临床上，RA患者表达的 水平高于健康个体。吸烟会使这种升高进一步加剧。总之，这些结果揭示了一种迄今未被认识的机制，通过该机制CS可能会加剧RA，并进一步推进对环境因素对慢性炎症性疾病发病机制影响的理解。
