title: The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is a chronic idiopathic disease of unknown etiology that is characterized by fibrosis of the skin and visceral organs mediated by activated myofibroblasts. The recently identified inflammasomes are cytosolic receptors that tightly regulate the activity of caspase 1 and downstream signaling molecules such as interleukin-1β (IL-1β) and IL-18. The nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome has been implicated in the development of idiopathic pulmonary fibrosis. This study was undertaken to assess the role of the inflammasome in SSc-related dermal or pulmonary fibrosis.
  
  
  METHODS
  Inflammasome gene transcripts were assayed in fibroblasts obtained from patients with SSc. Caspase 1 activation in SSc primary dermal and lung fibroblasts was inhibited, and the levels of hydroxyproline, COL1A1, COL3A1, IL-1β, IL-18, and α-smooth muscle actin (α-SMA) were measured. The role of the inflammasome in dermal fibrosis was investigated in NLRP3(-/-)  and ASC(-/-)  mice.
  
  
  RESULTS
  We identified increased expression of 40 genes associated with the inflammasome or downstream signaling molecules in SSc fibroblasts. Inhibition of caspase 1 in SSc dermal and lung fibroblasts abrogated the secretion of collagens, IL-1β, and IL-18. In addition, we observed decreased expression of the myofibroblast protein α-SMA in SSc dermal fibroblasts treated with a caspase 1 inhibitor. Furthermore, NLRP3(-/-)  mice and ASC(-/-)  mice were resistant to bleomycin-induced skin fibrosis, which suggests a key role for the inflammasome in in vivo fibrosis.
  
  
  CONCLUSIONS
  Innate immune signaling contributes to SSc fibrosis via activation of the inflammasome and caspase 1. These results suggest that inflammasome activation may play an important role in the pathogenesis of SSc.
authors.affiliation: Drexel University College of Medicine, Philadelphia, Pennsylvania, USA. carol.artlett@drexelmed.edu
authors.forename: Carol M
authors.initials: CM
authors.lastname: Artlett
authors.forename: Sihem
authors.initials: S
authors.lastname: Sassi-Gaha
authors.forename: Judy L
authors.initials: JL
authors.lastname: Rieger
authors.forename: Alina C
authors.initials: AC
authors.lastname: Boesteanu
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: Peter D
authors.initials: PD
authors.lastname: Katsikis
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D005355:Fibrosis; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000276:immunology* / Q000473:pathology
chemical_list: D058847:Inflammasomes; D020170:Caspase 1