Involvement of Type I Interferon Signaling in Muscle Stem Cell Proliferation During Dermatomyositis

Abstract

Background and objective:The idiopathic inflammatory myopathy Dermatomyositis (DM) is an acquired disease that combines muscle, lung and skin impairments. DM patients show a wide range of severity of proximal skeletal muscle weakness, associated with inflammatory infiltrates, vasculitis, and capillary dropout, perifascicular myofiber atrophy. Moreover, DM muscles show signs of muscle regeneration. Since muscle stem cells (MuSCs) are responsible for myofiber repair, we asked wether the proliferative properties of muscle stem cells (MuSCs) are altered in DM muscle. We investigated the role of type-I interferon (IFN-I) in this process since DM is associated with sustained inflammation with high IFN-I levels.Methods:MuSCs isolated from normal, adult and juvenile DM muscles were grown in culture and were analyzed in vitro for their proliferating properties, their myogenic capacities and their senescence. Gain and loss of function experiments were performed to assess the role of IFN-I signaling in the prolfierative capacities of MuSCs.Results:MuSCs derived from 8 DM adult patients (DM-MuSCs) (5 severe form and 3 mild form, established from histological evaluation), from 3 juvenile DM patients and from normal muscle were used to analyze their myogenesis in vitro. DM-MuSCs exhibited strongly reduced proliferating capacities as compared with healthy MuSCs (-31 to -43% for severe and mild DM, respectively), leading to poor myotube formation (-36 to -71%). DM-MuSCs were enriched in senescent, beta-galactosidase positive cells, explaining partly the proliferation defect. Gain and loss of function experiments were performed to assess the role of IFN-I on the proliferative capacity of MuSCs. High concentrations of IFN-I decreased the proliferation of healthy MuSCs. Similarly, conditioned-medium from DM-MuSCs decreased the proliferation of healthy MuSC (-15 to -22%), suggesting the delivery of an autocrine effector. Then, pharmacological blockade of the IFN signaling (using ruxolitinib or anti-IFN-receptor antibodies) in DM-MuSCs rescued their proliferation up to the control values.Discussion:These results show that autocrine IFN-I signaling prevents MuSC expansion, leading to muscle repair deficit. This process may explain the persistent muscle weakness observed in severe DM patients.

Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies

“…Analysis of muscle biopsies from dermatomyositis patients showed that in the advanced stage of perifascicular atrophy there is a perturbation of MRFs expression, characterized by an increase in Pax7 and Myogenin, but not MyoD [ 128 ]. Recently, a study showed that MuSCs isolated from muscle biopsies of patients with dermatomyositis have reduced proliferation and differentiation compared with healthy controls [ 129 ]. These cells exhibit higher levels of senescence markers that could partly explain their proliferative defects ( Figure 2 ).…”

“…These cells exhibit higher levels of senescence markers that could partly explain their proliferative defects ( Figure 2 ). Considering that dermatomyositis is associated with sustained inflammation characterized by high levels of IFN-I [ 126 ], the authors performed loss- and gain-of-function experiments to demonstrate that high levels of IFN-I decrease the proliferation of MuSCs, while pharmacological inhibition of IFN signaling rescued the proliferation of MuSCs from dermatomyositis patients [ 129 ]. These findings suggest that the detrimental effect of dermatomyositis in MuSC function is mediated, at least in part, by paracrine factors.…”

Update on dermatomyositis

“…Immunohistochemical co-expression of MxA with vascular endothelial growth factor (VEGF) and MxA staining on tubuloreticular inclusions (TRIs) supported IFN1 pathway activation as an underlying mechanism for dermatomyositis vasculopathy and TRI formation [3,60–62]. IFN1 exposure decreased muscle stem cells’ (MuSC) proliferation; impaired myoblasts differentiation and fusion; induced myotubes atrophy and IFN-α production; and impaired endothelial cells angiogenesis [60,63,64 ▪▪ ]. Blocking IFN1-signaling cascade via Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway activation by antiinterferon alpha-beta receptor, anti-IFN-α, anti-IFN-β, and ruxolitinib (preferentially JAK1 and JAK2 inhibitors), prevented and reversed these effects in muscle and endothelial cells [64 ▪▪ ,65 ▪ ,66,67].…”

“…IFN1 exposure decreased muscle stem cells’ (MuSC) proliferation; impaired myoblasts differentiation and fusion; induced myotubes atrophy and IFN-α production; and impaired endothelial cells angiogenesis [60,63,64 ▪▪ ]. Blocking IFN1-signaling cascade via Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway activation by antiinterferon alpha-beta receptor, anti-IFN-α, anti-IFN-β, and ruxolitinib (preferentially JAK1 and JAK2 inhibitors), prevented and reversed these effects in muscle and endothelial cells [64 ▪▪ ,65 ▪ ,66,67]. Interestingly, normal MuSC showed proliferation defect after exposure to dermatomyositis MuSC culture medium supernatant; adding ruxolitinib into the medium prevented the proliferation defect [64 ▪▪ ].…”

Type I Interferons in Dermatomyositis Myoblasts

“…In a study in the current issue of Neurology® , Gallay et al 8 provide further evidence of the importance of the IFN-I pathway in the pathogenesis of dermatomyositis by (1) delineating toxic effects of IFN-β on dermatomyositis-derived human skeletal muscle myoblasts and (2) reverting pathogenic effects of IFN-β with nonspecific (JAK/STAT inhibitors) and specific (blockade of the IFN-I receptor) IFN-I–pathway inhibitors.…”