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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE255031 | GEO | 2024/04/30

REPOSITORIES: GEO