Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis

Grönberg C, Rattik S, Tran-Manh C, Zhou X, Rius Rigau A, Li YN, Györfi AH, Dickel N, Kunz M, Kreuter A, Matei EA, Zhu H, Skoog P, Liberg D, Distler JH, Trinh-Minh T (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Article Number: 225158

DOI: 10.1136/ard-2023-225158

Abstract

Background: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). Methods: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. Results: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. Conclusion: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

Authors with CRIS profile

Aleix Rius Rigau Department of Medicine 3 – Rheumatology and Immunology Nicholas Dickel Lehrstuhl für Medizinische Informatik Meik Kunz Lehrstuhl für Medizinische Informatik

Involved external institutions

Universitätsklinikum Düsseldorf DE Germany (DE) Cantargia AB SE Sweden (SE) Universität Witten/Herdecke DE Germany (DE) Central South University CN China (CN)

How to cite

APA:

Grönberg, C., Rattik, S., Tran-Manh, C., Zhou, X., Rius Rigau, A., Li, Y.N.,... Trinh-Minh, T. (2024). Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Annals of the Rheumatic Diseases. https://doi.org/10.1136/ard-2023-225158

MLA:

Grönberg, Caitríona, et al. "Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis." Annals of the Rheumatic Diseases (2024).

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