Abstract
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and excessive fibrosis of the skin and internal organs. To this day, no effective treatments to prevent the progression of fibrosis exist, and SSc patients have disabilities and reduced life expectancy. The need to better understand pathways that drive SSc and to find therapeutic targets is urgent. RNA sequencing data from SSc dermal fibroblasts suggested that melanin-concentrating hormone receptor 1 (MCHR1), one of the G protein-coupled receptors regulating emotion and energy metabolism, is abnormally deregulated in SSc. Platelet-derived growth factor (PDGF)-BB stimulation upregulated MCHR1 mRNA and protein levels in normal human dermal fibroblasts (NHDF), and MCHR1 silencing prevented the PDGF-BB-induced expression of the profibrotic factors transforming growth factor beta 1 (TGFβ1) and connective tissue growth factor (CTGF). PDGF-BB bound MCHR1 in membrane fractions of NHDF, and the binding was confirmed using surface plasmon resonance (SPR). MCHR1 inhibition blocked PDGF-BB modulation of intracellular cyclic adenosine monophosphate (cAMP). MCHR1 silencing in NHDF reduced PDGF-BB signaling. In summary, MCHR1 promoted the fibrotic response in NHDF through modulation of TGFβ1 and CTGF production, intracellular cAMP levels, and PDGF-BB-induced signaling pathways, suggesting that MCHR1 plays an important role in mediating the response to PDGF-BB and in the pathogenesis of SSc. Inhibition of MCHR1 should be considered as a novel therapeutic strategy in SSc-associated fibrosis.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and excessive fibrosis of the skin and internal organs [1]
We determined that Melanin-Concentrating Hormone Receptor 1 (MCHR1) was a hub gene significantly upregulated in our network analysis (Supplementary Table 4 and Supplementary Figure 2), suggesting MCHR1 might play a pivotal role in the pathogenesis of SSc based on the “centrality principle” stating that highly connected vertices are often functionally important in biological systems [34]
To confirm the upregulation of MCHR1 in SSc patients, we examined MCHR1 mRNA levels in dermal fibroblasts from SSc patients with early disease compared to fibroblasts from healthy subjects using quantitative PCR
Summary
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and excessive fibrosis of the skin and internal organs [1]. Skin fibrosis is the most common finding in SSc patients and can be associated with fibrosis of internal organs, which results in high mortality [2, 3]. Fibroblasts are considered the effector cells in fibrosis [4]. Several growth factors, such as transforming growth factor beta (TGFb) [5], connective tissue growth factor (CTGF) [6] and platelet-derived growth factor (PDGF), can activate the profibrotic response of fibroblasts and contribute to the pathogenesis of SSc [7]. Aberrant MCHR1 expression is reported in lung tissues of patients with idiopathic pulmonary fibrosis, which has clinical and pathogenic features that overlap with SSc-associated interstitial lung disease [17]. Our goal was to elucidate the role of MCHR1 signaling in dermal fibroblast activation
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