Key result
JAK inhibitors and epigenetic modulators potently inhibit the type I IFN-MHC class I pathway in myoblasts.
Why the study?
Immunosuppressants used to treat autoimmunity are often not curative and cause many side effects, creating a need for new therapeutics targeting the type I IFN-MHC class I pathway in idiopathic inflammatory myopathies.
High-throughput screening identified Janus kinase inhibitors (e.g., ruxolitinib) and epigenetic modulators as potent inhibitors of the type I IFN-MHC class I pathway in human myoblasts, offering potential therapeutic candidates for myositis.
Ruxolitinib and epigenetic modulators merit myositis model testing; leaves open clinical translation from myoblast screening.
Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows that the pro-inflammatory type I interferons (IFN) and a downstream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high-throughput screening on >4500 compounds, including all approved drugs, through a series of cell-based assays to identify those that inhibit the type I IFN-MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblasts containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors, with the most potent being ruxolitinib, and epigenetic/transcriptional modulators like histone deacetylase inhibitors and the hypoxia-inducible factor 1 inhibitor echinomycin. Testing in animal models and clinical trials is necessary to translate these therapies to myositis patients. These robust assay technologies can be further utilized to interrogate the basic mechanisms of the type I IFN-MHC class I pathway, identify novel molecular probes, and elucidate possible environmental triggers that may lead to myositis.
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Kinder et al. (2020) studied Idiopathic inflammatory myopathies (myositis). High-throughput screening of >4500 compounds was evaluated on Inhibition of the type I IFN-MHC class I pathway in muscle precursor cells. High-throughput screening identified Janus kinase inhibitors, including ruxolitinib, and epigenetic modulators as potent inhibitors of the type I IFN-MHC class I pathway in human myoblasts.
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