Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, China.
Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, China; Department of Dermatology, Hunan Children's Hospital, Changsha 410000, Hunan, China.
Int Immunopharmacol. 2020 Nov;88:106886. doi: 10.1016/j.intimp.2020.106886. Epub 2020 Aug 12.
Systemic sclerosis (SSc) is a systemic autoimmune disease that often leads to fibrosis of multiple organs, and there are no effective treatments. Aryl hydrocarbon receptor (AhR) is a highly evolutionarily conserved transcription factor activated by endogenous and exogenous ligands and that regulate cell proliferation, tumorigenesis and immune balance. Recently, it have reported AhR signaling may participate in fibrosis process, usually consider as a negative regulator of TGF-β. However, the detailed relationship between AhR and SSc has not been reported yet. Here we firstly found that AhR and CYP1A1 downregulated in SSc fibroblast(n = 6). The AhR ligand-Ficz negatively regulates TGF-β1, COL1A1 and α-SMA expression, also enhances the MMP-1 expression via the AhR signaling activation. Conversely the AhR antagonist CH223191 could inhibit this effect. Furthermore, the antifibrosis effect of AhR signaling activation was also confirmed in bleomycin induced scleroderma mouse model. In conclusion, AhR signaling activation balances the extracellular matrix (ECM) composition and deposition, which may provide a new sight to the pathogenesis of SSc and AhR signaling activation may be a potential therapy for SSc.
系统性硬化症（SSc）是一种系统性自身免疫性疾病，常导致多个器官纤维化，目前尚无有效治疗方法。芳烃受体（AhR）是一种高度进化保守的转录因子，可被内源性和外源性配体激活，调节细胞增殖、肿瘤发生和免疫平衡。最近有报道称，AhR 信号可能参与纤维化过程，通常被认为是 TGF-β的负调节剂。然而，AhR 与 SSc 之间的详细关系尚未报道。在这里，我们首次发现 AhR 和 CYP1A1 在 SSc 成纤维细胞中下调（n=6）。AhR 配体-Ficz 负调节 TGF-β1、COL1A1 和 α-SMA 的表达，也通过 AhR 信号激活增强 MMP-1 的表达。相反，AhR 拮抗剂 CH223191 可以抑制这种作用。此外，AhR 信号激活的抗纤维化作用也在博来霉素诱导的硬皮病小鼠模型中得到了证实。总之，AhR 信号激活平衡细胞外基质（ECM）的组成和沉积，这可能为 SSc 的发病机制提供新的视角，并且 AhR 信号激活可能是 SSc 的一种潜在治疗方法。
