PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

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 bette...

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Autores principales:	Naoko Takamura, Ludivine Renaud, Willian Abraham da Silveira, Carol Feghali-Bostwick
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	scleroderma systemic sclerosis skin fibrosis MCHR1 PDGF fibroblast Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/c60a2da41f0a443583523305d072b611
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spelling	oai:doaj.org-article:c60a2da41f0a443583523305d072b6112021-12-01T13:37:15ZPDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR11664-322410.3389/fimmu.2021.745308https://doaj.org/article/c60a2da41f0a443583523305d072b6112021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.745308/fullhttps://doaj.org/toc/1664-3224Systemic 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.Naoko TakamuraLudivine RenaudWillian Abraham da SilveiraCarol Feghali-BostwickFrontiers Media S.A.articlesclerodermasystemic sclerosisskin fibrosisMCHR1PDGFfibroblastImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	scleroderma systemic sclerosis skin fibrosis MCHR1 PDGF fibroblast Immunologic diseases. Allergy RC581-607
spellingShingle	scleroderma systemic sclerosis skin fibrosis MCHR1 PDGF fibroblast Immunologic diseases. Allergy RC581-607 Naoko Takamura Ludivine Renaud Willian Abraham da Silveira Carol Feghali-Bostwick PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
description	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.
format	article
author	Naoko Takamura Ludivine Renaud Willian Abraham da Silveira Carol Feghali-Bostwick
author_facet	Naoko Takamura Ludivine Renaud Willian Abraham da Silveira Carol Feghali-Bostwick
author_sort	Naoko Takamura
title	PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
title_short	PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
title_full	PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
title_fullStr	PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
title_full_unstemmed	PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1
title_sort	pdgf promotes dermal fibroblast activation via a novel mechanism mediated by signaling through mchr1
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c60a2da41f0a443583523305d072b611
work_keys_str_mv	AT naokotakamura pdgfpromotesdermalfibroblastactivationviaanovelmechanismmediatedbysignalingthroughmchr1 AT ludivinerenaud pdgfpromotesdermalfibroblastactivationviaanovelmechanismmediatedbysignalingthroughmchr1 AT willianabrahamdasilveira pdgfpromotesdermalfibroblastactivationviaanovelmechanismmediatedbysignalingthroughmchr1 AT carolfeghalibostwick pdgfpromotesdermalfibroblastactivationviaanovelmechanismmediatedbysignalingthroughmchr1
_version_	1718405137887657984

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

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