Transcriptomics of autoimmune diseases identifies FGFR1 as a target for pancreatic β-cell protection

Abstract

Autoimmune diseases, such as type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), are often studied from an immune perspective with less focus on the target tissue responses. Target tissues, however, are key to disease and engage in a harmful crosstalk with the immune system contributing to their own destruction. We presently integrated transcriptomic data from the target tissues of six autoimmune/inflammatory diseases affecting β-cells (T1D and type 2 diabetes), thyroid (HT), brain (multiple sclerosis and Alzheimer's disease) or the joints (rheumatoid arthritis), using both bulk and single-cell/nucleus RNA-sequencing (sc/snRNA-seq) approaches. Common upregulated pathways were associated with innate/adaptive immunity, antigen presentation and interferon (IFN) signaling. The role of IFNs was confirmed by RNA-seq in human insulin-producing EndoC-βH1 cells and stem cell-derived thyroid follicle cells exposed to IFNα or IFNγ. Commonly upregulated inflammatory gene signatures were explored, and fibroblast growth factor receptor (FGFR) inhibitors emerged as a potential strategy to counteract these inflammatory transcriptional signatures. The effects of the FGFR1 inhibitor PD173074 on IFN-induced immune related genes were evaluated in EndoC-βH1 cells, stem cell-derived islets and adult human islets. We validated the FGFR inhibitor PD173074 as a promising drug for preserving expression of β-cell protective genes (PDL1 and HLA-E) while reducing HLA class I expression and β-cell recognition by diabetogenic pre-proinsulin-specific CD8⁺ T-cells. In conclusion, we integrated transcriptomic data from the target tissues of autoimmune and inflammatory/degenerative diseases and departing from these data identified the potential beneficial effects of FGFR inhibitors in T1D.

Keywords: Drug repurposing; Fibroblast growth factor receptor 1; Hashimoto's thyroiditis; Interferons; Pancreatic β-cells; Thyroid follicular cells; Type 1 diabetes.