PDGF-BB Promotes Type I IFN-Dependent Vascular Alterations and Monocyte Recruitment in a Model of Dermal Fibrosis.
Systemic sclerosis (SSc) is a chronic autoimmune disorder that can result in extensive tissue damage in the skin and, in advanced cases, internal organs. Vasculopathy, aberrant immune activation, and tissue fibrosis are three hallmarks of the disease that have been identified, with vasculopathy and aberrant immunity being amongst the earliest events. However, a mechanistic link between these processes has not been established. Here, we have identified a novel role of platelet derived growth factor-BB (PDGF-BB)/PDGFRβ activation in combination with dermal injury induced by bleomycin as a driver of early, aberrant expression of interferon stimulatory genes (ISGs) and inflammatory monocyte infiltration. Activation of PDGFRβ in combination with bleomycin-induced dermal injury resulted in increased dermal thickness, vascular density, monocyte/macrophage infiltration, and exacerbation of tissue injury. Many of these features were dependent on IFNAR-signaling, and an increase in the number of interferon-beta (IFN-β) producing monocytes cells was found in the skin lesions. Taken together, these results identify a novel link between PDGFRβ activation, and Type I IFN-driven vascular maintenance and monocyte/macrophage cell recruitment, and provide a potential explanation linking key features of SSc that were previously thought to be unrelated.
Immunology Research, Biogen, Cambridge, MA, United States of America.
John S
JS
Cho
Immunology Research, Biogen, Cambridge, MA, United States of America.
Terry C
TC
Fang
Translational Sciences - Pathology, Biogen, Cambridge, MA, United States of America.
Taylor L
TL
Reynolds
Translational Sciences - Pathology, Biogen, Cambridge, MA, United States of America.
Daniel J
DJ
Sofia
Translational Sciences - Pathology, Biogen, Cambridge, MA, United States of America.
Stefan
S
Hamann
Immunology Research, Biogen, Cambridge, MA, United States of America.
Linda C
LC
Burkly
D000818:Animals; D000077214:Becaplermin; D001761:Bleomycin / Q000494:pharmacology; D001808:Blood Vessels / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis; D007370:Interferon Type I / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000473:pathology*; D012871:Skin Diseases / Q000473:pathology*
D007370:Interferon Type I; D020574:Proto-Oncogene Proteins c-sis; D001761:Bleomycin; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta