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Войти в исследования Annals of the rheumatic diseases · 2026
Inhibition of the type I interferon receptor pathway protects against muscle weakness induced by dermatomyositis serum.
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Kaewin Suchada, Leijding Cecilia, Gastaldello Stefano, Makari David, Zhong Yi, Andreasson Kristofer M, Jardemark Kent, Dastmalchi Maryam, Horuluoglu Begum, Alexanderson Helene, Lauschke Volker M, Lundberg Ingrid E, Andersson Daniel C
Аннотация
OBJECTIVES: Dermatomyositis (DM) is characterised by systemic inflammation, debilitating muscle weakness, cutaneous lesions, and increased mortality. An upregulation of type I interferon (IFN)-stimulated genes is observed in patients with DM. However, it remains unclear whether type I IFNs cause muscle weakness in DM. This study aimed to investigate the role of IFN-α/β receptor signalling in muscle weakness induced by factors in DM serum.
METHODS: In ex vivo experiments, flexor digitorum brevis muscles were isolated from healthy mice and incubated 24 hours with 10% healthy serum or serum from patients with DM (n = 9). To modulate IFN signalling, an antibody against the type I IFN receptor α/β subunit 1 (IFNAR1) or the Janus kinase-signal transducer and activator of transcription inhibitor ruxolitinib was used. RNA sequencing, followed by bioinformatics analysis, was conducted to identify differentially expressed genes and affected pathways related to IFN signalling.
RESULTS: Incubation with serum from patients with DM, but not that from healthy controls, caused significant muscle weakness manifested by a reduction in muscle force. Bioinformatic analyses revealed downregulation of type I IFN-inducible genes with IFNAR1 antibody. Pathway analysis showed enrichment of several IFN-related pathways. Inhibition of type I IFN signalling with either an IFNAR1 antibody or ruxolitinib abolished DM serum-induced effects.
CONCLUSIONS: Factors in serum from patients with DM can activate the type I IFN signalling pathway in skeletal muscles, which constitutes an important causal factor for muscle weakness. Our data support a mechanistic model where blood-borne factors contribute to muscle disease phenotypes and underscore the therapeutic possibilities of pharmacological interventions targeting the IFNAR1 signalling pathway.
METHODS: In ex vivo experiments, flexor digitorum brevis muscles were isolated from healthy mice and incubated 24 hours with 10% healthy serum or serum from patients with DM (n = 9). To modulate IFN signalling, an antibody against the type I IFN receptor α/β subunit 1 (IFNAR1) or the Janus kinase-signal transducer and activator of transcription inhibitor ruxolitinib was used. RNA sequencing, followed by bioinformatics analysis, was conducted to identify differentially expressed genes and affected pathways related to IFN signalling.
RESULTS: Incubation with serum from patients with DM, but not that from healthy controls, caused significant muscle weakness manifested by a reduction in muscle force. Bioinformatic analyses revealed downregulation of type I IFN-inducible genes with IFNAR1 antibody. Pathway analysis showed enrichment of several IFN-related pathways. Inhibition of type I IFN signalling with either an IFNAR1 antibody or ruxolitinib abolished DM serum-induced effects.
CONCLUSIONS: Factors in serum from patients with DM can activate the type I IFN signalling pathway in skeletal muscles, which constitutes an important causal factor for muscle weakness. Our data support a mechanistic model where blood-borne factors contribute to muscle disease phenotypes and underscore the therapeutic possibilities of pharmacological interventions targeting the IFNAR1 signalling pathway.