Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.
Clinic for Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany.
Rheumatology (Oxford). 2021 Jun 18;60(6):3012-3022. doi: 10.1093/rheumatology/keaa747.
Functional IgG autoantibodies against diverse G protein-coupled receptors, i.e. antibodies with agonistic or antagonistic activity at these receptors, are abundant in human serum. Their levels are altered in patients with SSc, and autoantibodies against angiotensin II receptor 1 (ATR1) and endothelin receptor A (ETA) have been suggested to drive SSc by inducing the chemokines CXCL8 and CCL18 in the blood. The objective of our study is to profile the effect of IgG in SSc (SSc-IgG) on the production of soluble mediators in monocytic cells.
Monocyte-like THP-1 cells were stimulated with SSc-IgG and their secretome was analysed. Furthermore, the significance of major pro-inflammatory pathways for the induction of CXCL8 and CCL18 in response to SSc-IgG was assessed by a pharmacological approach.
Stimulation with SSc-IgG significantly alters the secretome of THP-1 cells towards a general pro-inflammatory and profibrotic phenotype, which includes an increase of CCL18 and CXCL8. The consequent expression profiles vary depending on the individual donor of the SSc-IgG. CCL18 and CXCL8 expression is thus regulated differentially, with AP-1 driving the induction of both CCL18 and CXCL8 and the TAK/IKK-β/NF-κB pathway and ERK1/2 driving that of CXCL8.
Our results suggest that SSc-IgG contributes to the generation of the pro-inflammatory/profibrotic tissue milieu characteristic of SSc by its induction of a respective phenotype in monocytes. Furthermore, our results highlight AP-1 as a critical regulator of gene transcription of CCL18 in monocytic cells and as a promising pharmacological therapeutic target for the treatment of SSc.
针对各种 G 蛋白偶联受体的功能性 IgG 自身抗体，即这些受体具有激动或拮抗活性的抗体，在人类血清中大量存在。它们在 SSc 患者中的水平发生改变，并且有人提出，针对血管紧张素 II 受体 1（ATR1）和内皮素受体 A（ETA）的自身抗体通过在血液中诱导趋化因子 CXCL8 和 CCL18 来驱动 SSc。本研究的目的是分析 SSc 中的 IgG（SSc-IgG）对单核细胞产生可溶性介质的影响。
用 SSc-IgG 刺激单核细胞样 THP-1 细胞，并分析其分泌组。此外，通过药理学方法评估主要促炎途径对 SSc-IgG 诱导 CXCL8 和 CCL18 的重要性。
用 SSc-IgG 刺激可显著改变 THP-1 细胞的分泌组，使其向一般的促炎和促纤维化表型转变，包括 CCL18 和 CXCL8 的增加。随后的表达谱因 SSc-IgG 的个体供体而异。因此，CCL18 和 CXCL8 的表达受到不同的调控，AP-1 驱动 CCL18 和 CXCL8 的诱导，TAK/IKK-β/NF-κB 途径和 ERK1/2 驱动 CXCL8 的诱导。
我们的结果表明，SSc-IgG 通过诱导单核细胞产生相应的表型，导致 SSc 中特征性的促炎/促纤维化组织微环境的产生。此外，我们的结果强调了 AP-1 作为单核细胞中 CCL18 基因转录的关键调节剂，以及作为治疗 SSc 的有前途的药理学治疗靶点。
