1185: Interleukin-11 Promotes Fibrosis Through Classic and Trans-signaling Pathway in Systemic Sclerosis

Wenjing Ye¹, Qian Wang¹, Li Zhao², Changcheng Wang³, Dandan Zhang⁴, Mengyu Zhou⁴, Fangfang Chen², Zaihua Zhu², Weiguo Wang², Wenyu Guo⁵, Yun Liu⁴, Hejian Zou² and Yu Xue², ¹epartment of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China, ²Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China, ³Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China, ⁴MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China, ⁵Clinical Development, I-Mab Biopharma (Hangzhou) Co., Ltd, Shanghai, China

Background/Purpose: Interleukin-11 (IL-11) was found significantly upregulated in Systemic sclerosis (SSc), the aim of this study is to explore the pathological role of IL-11 and clarify the potential therapeutic value of targeting IL-11 in SSc.

Methods: Plasma IL-11 level was tested by ELISA, and the expression of ADAM10, IL-11 and IL-11Rα in skin were measured by immunohistochemistry. RNA-Seq was performed to analyze the transcription change in IL-11 overexpressing fibroblast cells. Soluble IL-11Rα (sIL-11Rα) induced by ionomycin (iono) was used to evaluate the pro-fibrotic effect of IL-11 trans-signaling pathway in fibroblast. TJ301(sgp130Fc, an inhibitor of IL-11 trans-signaling) intervention group was set up to investigate the anti-fibrosis effect of targeting IL-11 trans-signaling pathway in both cellular and animal experiments. Meanwhile, WP1066 was used to block STAT3 pathway in cellular study.

Results: Plasma IL-11 level was extremely low in most SSc patients and healthy controls, while IL-11, IL-11Rα and ADAM10 were significantly elevated in skin samples of SSc patients. RNA-Seq analysis displayed some fibrotic-related genes were dysregulated in IL-11 overexpressing cells, and differentially expressed genes (DEGs) were enriched in TGF-β effect and collagen metabolism pathway. Fibroblasts stimulated with IL-11 with iono could induce COL3 expression and STAT3 phosphorylation, and the pro-fibrotic effect could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM induced-SSc mice.

Conclusion: Besides classic signaling pathway, IL-11 contributes to pro-fibrosis in SSc through regulating trans-signaling pathway. Intervention of IL-11 trans-signaling pathway or JAK2/STAT3 pathway could ameliorate the pro-fibrotic response of IL-11.
Figure. Pro-fibrotic effect of IL-11.
Disclosures: W. Ye, None; Q. Wang, None; L. Zhao, None; C. Wang, None; D. Zhang, None; M. Zhou, None; F. Chen, None; Z. Zhu, None; W. Wang, None; W. Guo, None; Y. Liu, None; H. Zou, None; Y. Xue, None.