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| Status |
Public on Apr 30, 2024 |
| Title |
Combined inhibition of IL-1, IL-33 and IL-36 signaling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of Systemic Sclerosis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background: The IL-1 receptor accessory protein (IL1RAP) is an essential co-receptor required for signaling 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 signaling molecules was determined by data mining of publicly available RNAseq data as well as by imaging mass cytometry (IMC). Efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complimentary mouse models: chronic sclerodermatous 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 signaling molecules on mRNA and protein level compared to normal skin. IL-1, IL-33, and IL-36 all regulate distinct genes 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-, bleomycin- 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 first evidence for the therapeutic benefits of targeting of IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase 1 clinical trial.
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| Overall design |
The allogeneically transplanted mice (cGVHD mice) were given i.p twice a week for 4 weeks of ddH2O (Allo_H), anti-mouse IL1RAP antibody (mCAN10), Nintedanib (Nin), or isotype mIgG2a LALA-PG antibody (Allo). The syngeneically transplanted mice treated with isotype mIgG2a LALA-PG antibody were used as control (Syn).
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| Contributor(s) |
Trinh-Minh T, Distler J, Rattik S, Grönberg C |
| Citation(s) |
38594058 |
| |
| Submission date |
Feb 04, 2024 |
| Last update date |
Jul 30, 2024 |
| Contact name |
Jörg Distler |
| E-mail(s) |
[email protected]
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| Organization name |
University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University
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| Department |
Department of Rheumatology
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| Lab |
Hiller Research Center
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| Street address |
Merowingerplatz 1A
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| City |
Düsseldorf |
| ZIP/Postal code |
40225 |
| Country |
Germany |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA1073269 |
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