Abstract
Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-β was observed in hypoxic conditions. Finally, HIF-1α overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors.
Highlights
Dermatomyositis (DM) is an inflammatory myopathy affecting skin and skeletal muscle
To investigate the possible effect of hypoxia in the transcriptomic induction of genes that belong to the IFN-I signature and previously related with DM12, 13, we searched for the presence of hypoxia response elements (HRE) in regulatory regions of those genes
We show that high levels of retinoic acid-inducible gene I (RIG-I) induce the signalling cascade that activates the transcription of IFN-I and we report the expression of HIF-1α in muscle fibers in DM
Summary
Dermatomyositis (DM) is an inflammatory myopathy affecting skin and skeletal muscle. The pathogenesis of DM is complex, comprising both immune and non-immune mechanisms. When oxygen is decreased, HIF-1α forms a heterodimer with HIF-1β, that escapes prolyl hydroxylation, and translocates to the nucleus and binds to hypoxia-response elements (HRE) present in the regulatory regions of hypoxia-inducible genes[6]. These genes are involved in metabolic adaptation (glycogen synthase7), angiogenesis (VEGF), and intriguingly, inflammation[8]. Since capillary loss is observed in DM muscle we hypothesized that HIF-1α can be stabilized and activate hypoxia inducible genes. Since our in silico analysis demonstrated that RIG-I contains HRE in its regulatory regions, we aimed to study if RIG-I expression may be regulated by hypoxia and the effects of that modulation using an in vitro approach
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