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. 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.

NLRP3 Inflammasome Is a Target for Development of Broad-Spectrum Anti-Infective Drugs

“…Normal primary human fibroblasts (GM5659) obtained from the Coriell Institute (Camden, NJ) were cultured in 70-mm dishes as previously described (5). Mouse fibroblasts were established from C57BL/6 (Jackson Laboratories) and NLRP3 Ϫ/Ϫ and ASC Ϫ/Ϫ mice (gift from Genentech, South San Francisco, CA).…”

NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung

“…Interestingly, it has been postulated that pharmacologically induced NLRP3 activation leads to interstitial lung disease [17]. Caspase-1 activity has also been directly linked to systemic sclerosis-related fibrosis, which suggests that autocrine signalling mediated by IL-1β and IL-18 promotes the pro-fibrotic phenotype observed in these patients [18]. Moreover, NLRP3 inflammasome activation has been linked to neutrophilic asthma [19], while inflammasome-regulated cytokines are critical mediators of acute lung injury [20].…”

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE 2 .Ki Mice Fed a High-Fat Diet

“…It is activated in response to a variety of signals that are indicative of damage to the host, including tissue damage, metabolic stress, and infection. [14][15][16] It is well known that sterile inflammation is a crucial event in the pathological process that underlies atherosclerosis, 17 whereas the role of inflammasomes in this process is still poorly explored. Cholesterol crystals (CCs) are important inflammatory stimuli in atherosclerosis development, acting as an endogenous danger signal via the NRLP3 inflammasome.…”