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. CONCLUSION: 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.
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. CONCLUSION: 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: James D Thacker; Brian J Balin; Denah M Appelt; Sihem Sassi-Gaha; Mitali Purohit; Richard F Rest; Carol M Artlett Journal: Antimicrob Agents Chemother Date: 2012-01-30 Impact factor: 5.191
Authors: Debendra Pattanaik; Monica Brown; Bradley C Postlethwaite; Arnold E Postlethwaite Journal: Front Immunol Date: 2015-06-08 Impact factor: 7.561
Authors: Nathan A Bracey; Benjamin Gershkovich; Justin Chun; Akosua Vilaysane; H Christopher Meijndert; James R Wright; Paul W Fedak; Paul L Beck; Daniel A Muruve; Henry J Duff Journal: J Biol Chem Date: 2014-05-19 Impact factor: 5.157