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
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Annals of the rheumatic diseases - (2024) vom: 09. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Grönberg, Caitríona [VerfasserIn] |
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| Links: |
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| Themen: |
Fibroblasts |
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| Anmerkungen: |
Date Revised 09.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1136/ard-2023-225158 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370833937 |
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| 041 | |a eng | ||
| 100 | 1 | |a Grönberg, Caitríona |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
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| 500 | |a Date Revised 09.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR. | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Fibroblasts | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Pulmonary Fibrosis | |
| 650 | 4 | |a Scleroderma, Systemic | |
| 700 | 1 | |a Rattik, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Tran-Manh, Cuong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Rius Rigau, Aleix |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yi-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Györfi, Andrea-Hermina |e verfasserin |4 aut | |
| 700 | 1 | |a Dickel, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Kunz, Meik |e verfasserin |4 aut | |
| 700 | 1 | |a Kreuter, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Matei, Emil-Alexandru |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Honglin |e verfasserin |4 aut | |
| 700 | 1 | |a Skoog, Petter |e verfasserin |4 aut | |
| 700 | 1 | |a Liberg, David |e verfasserin |4 aut | |
| 700 | 1 | |a Distler, Jörg Hw |e verfasserin |4 aut | |
| 700 | 1 | |a Trinh-Minh, Thuong |e verfasserin |4 aut | |
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