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High throughput screening to identify inhibitors of the type I interferon - major histocompatibility complex class I pathway in skeletal muscle.
ACS Chemical Biology 2020 May 28
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 the pro-inflammatory type I interferons (IFN) and a down-stream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high throughput screening on >4,500 compound titrations, 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 myoblast 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 are 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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