Abstract
Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. In vitro, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.
Highlights
We have previously reported in diabetic cardiomyopathy, a co-morbid inflammation driven condition, that CXCL10 is a pharmacologic target of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), originally employed to treat erectile dysfunction and more commonly used in systemic sclerosis (SSc) both for the management of Raynaud’s phenomenon (RP) and pulmonary artery hypertension (PAH), on the basis of its vascular effects [17,18,19,20,21]
We showed that CXCL10 serum level was significantly lower in SSc patients taking sildenafil compared to SSc patients on no sildenafil
CXCL10 release in human skeletal muscle cells under inflammatory challenge, we evaluated Signal transducer and activator of transcription 1 (STAT1), Jun N-terminal kinase (JNK) and NF-kB phosphorylation induced by IFNγ+TNFα in human fetal skeletal muscle cells (Hfsmc), human dermal fibroblasts (Hdfbs), and, for comparison with other striated cells, in human fetal cardiomyocytes (Hfcm) with or without sildenafil (1 μM)
Summary
C-X-C chemokine ligand 10 CXCL10, a main interferon (IFN)-γ inducible protein, recognized as a type I IFN inducible biomarker, plays a critical role in the pathogenesis and progression of several autoimmune diseases, including systemic sclerosis (SSc) [1,2]. It is reported that SSc patients with higher CXCL10 sera levels show worse skin involvement and a higher degree of clinical severity, as measured by Medsger severity scales [11,12,13]. A common feature contributing to the worse prognosis of SSc is the involvement of muscle tissue [14,15], either limited to peripheral muscle or extended to cardiomyopathy (id est, left ventricular cardiac dysfunction and or arrhythmia), both of which have been associated with increased CXCL10 levels in the blood [16,17,18]. We investigated the molecular effect of sildenafil in human myocytes secreting CXCL10 under Type 1 T helper (Th1) challenge in vitro
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