☆ 4.5 Article

Myogenic Progenitor Cells Exhibit Type I Interferon-Driven Proangiogenic Properties and Molecular Signature During Juvenile Dermatomyositis

ARTHRITIS & RHEUMATOLOGY (2018)

Journal

ARTHRITIS & RHEUMATOLOGY

Volume 70, Issue 1, Pages 134-145

Publisher

WILEY

DOI: 10.1002/art.40328

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Funding

INSERM
CNRS
Universite Paris Descartes
Universite Claude Bernard Lyon 1
European Union Seventh Framework Programme (project Endostem) [241440]
Association Francaise contre les Myopathies [18003]
Poste d'Accueil fellowship from AP-HP/CNRS

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Abstract

ObjectiveJuvenile dermatomyositis (JDM) is an inflammatory pediatric myopathy characterized by focal capillary loss in muscle, followed by progressive recovery upon adequate treatment with immunomodulating drugs, although some patients remain refractory to treatment. While the underlying mechanism of capillary depletion remains uncertain, recent studies have identified an up-regulation of type I interferon (IFN) expression specific to JDM. Given that myogenic precursor cells (MPCs) exert proangiogenic activity during normal skeletal muscle regeneration, we hypothesized that they may also modulate vascular remodeling/angiogenesis during JDM. The aim of this study was to investigate that hypothesis. MethodsHuman cell cocultures were used to analyze angiogenic properties in patients with JDM, patients with Duchenne's muscular dystrophy (DMD) (control patients for vascular remodeling), and healthy control subjects. Transcriptome analysis was used to examine muscle-derived MPCs. Histologic analysis of type I IFN in muscle biopsy samples was also performed. ResultsUsing human cell cocultures, we showed highly angiogenic properties of MPCs from JDM patients in association with the expression of an angiogenic molecular signature. Transcriptome analysis of MPCs freshly isolated from muscle samples revealed type I IFN as the master regulator of the most up-regulated genes in JDM-derived MPCs. Functionally, treatment of normal MPCs with type I IFN recapitulated the molecular pattern and the proangiogenic functions of JDM-derived MPCs. In vivo histologic investigation showed that MPCs synthesized type I IFN and major proangiogenic molecules in JDM muscle. Moreover, MPCs derived from JDM muscles that were characterized by strong vasculopathy produced higher levels of type I IFN, confirming MPCs as a cellular source of type I IFN during JDM, and this correlated with the severity of the disease. ConclusionThese results demonstrate a new type I IFN pathway in JDM that activates the production of angiogenic effectors by MPCs, triggering their proangiogenic function to promote vessel recovery and muscle reconstruction.

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Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response

Butsabong Lerkvaleekul, Saskia R. Veldkamp, Maria M. van der Wal, Ellen J. H. Schatorje, Sylvia S. M. Kamphuis, J. Merlijn van den Berg, Petra C. E. Hissink Muller, Wineke Armbrust, Sebastiaan J. Vastert, Judith Wienke, Marc H. A. Jansen, Annet Van Royen-Kerkhof, Femke van Wijk

Summary: Siglec-1 on monocytes is identified as a novel IFN-inducible biomarker in JDM, correlating with clinical disease activity and predicting treatment response. Patients with high Siglec-1 expression at diagnosis have a higher risk of requiring treatment intensification, and Siglec-1 expression is superior to the IFN score in predicting treatment response.

RHEUMATOLOGY (2022)