2. Academic Validation
  3. 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

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

  • Ann Rheum Dis. 2024 Aug 27;83(9):1156-1168. doi: 10.1136/ard-2023-225158.
Caitríona Grönberg # 1,  Sara Rattik # 1,  Cuong Tran-Manh 2 3,  Xiang Zhou 2 3,  Aleix Rius Rigau 4,  Yi-Nan Li 2 3,  Andrea-Hermina Györfi 2 3,  Nicholas Dickel 5,  Meik Kunz 5,  Alexander Kreuter 6,  Emil-Alexandru Matei 2 3,  Honglin Zhu 7,  Petter Skoog 1,  David Liberg 1,  Jörg Hw Distler # 8 3,  Thuong Trinh-Minh # 2 3
Affiliations

Affiliations

  • 1 Cantargia AB, Lund, Sweden.
  • 2 Department of Rheumatology, University Hospital of Düsseldorf, Düsseldorf, Nordrhein-Westfalen, Germany.
  • 3 Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, NRW, Germany.
  • 4 Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Bayern, Germany.
  • 5 Chair of Medical Informatics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.
  • 6 Department of Dermatology, Venereology, and Allergology, HELIOS Saint Elisabeth Hospital Oberhausen, University Witten-Herdecke, Oberhausen, Nordrhein-Westfalen, Germany.
  • 7 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 8 Department of Rheumatology, University Hospital of Düsseldorf, Düsseldorf, Nordrhein-Westfalen, Germany [email protected].
  • # Contributed equally.
PMID: 38594058 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.

Keywords

Fibroblasts; Inflammation; Pulmonary Fibrosis; Scleroderma, Systemic.

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