The Inflammasome Activating Caspase 1 Mediates Fibrosis and Myofibroblast Differentiation in Systemic Sclerosis
The Inflammasome Activating Caspase 1 Mediates Fibrosis and Myofibroblast Differentiation in Systemic Sclerosis
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DOI：
10.1002/art.30568
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发表时间：
2011-11-01
影响因子：
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通讯作者：
Katsikis, Peter D.
中科院分区：
文献类型：
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作者：
Artlett, Carol M.;Sassi-Gaha, Sihem;Katsikis, Peter D.
Objective.系统性硬化症（SSc）是一种病因不明的慢性特发性疾病，其特征是由活化的肌成纤维细胞介导的皮肤和内脏器官纤维化。最近鉴定的炎性小体是细胞溶质受体，其紧密调节胱天蛋白酶1和下游信号分子如白细胞介素-1 β（IL-1 β）和IL-18的活性。核苷酸结合寡聚化结构域（NOD）样受体3（NLRP 3）炎性体与特发性肺纤维化的发生有关。本研究旨在评估炎性小体在Ssc相关皮肤或肺纤维化中的作用。在从SSc患者获得的成纤维细胞中测定炎性体基因转录物。SSc原代真皮和肺成纤维细胞中的半胱天冬酶1活化被抑制，并测量羟脯氨酸、COL 1A 1、COL 3A 1、IL-1 β、IL-18和α-平滑肌肌动蛋白（α-SMA）的水平。在NLRP 3（-/-）和ASC（-/-）小鼠中研究炎性小体在真皮纤维化中的作用。我们鉴定了40个与SSc成纤维细胞中炎性小体或下游信号分子相关的基因的表达增加。抑制SSc皮肤和肺成纤维细胞中的半胱天冬酶1可消除胶原、IL-1 β和IL-18的分泌。此外，我们观察到用半胱天冬酶1抑制剂处理的SSc真皮成纤维细胞中肌成纤维细胞蛋白α-SMA的表达降低。此外，NLRP 3（-/-）小鼠和ASC（-/-）小鼠对博莱霉素诱导的皮肤纤维化具有抵抗性，这表明炎性小体在体内纤维化中起关键作用。先天性免疫信号传导通过炎性体和半胱天冬酶1的激活促进SSc纤维化。这些结果表明，炎性小体激活可能在SSc的发病机制中起重要作用。
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-1 beta (IL-1 beta) 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-1 beta, IL-18, and alpha-smooth muscle actin (alpha-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-1 beta, and IL-18. In addition, we observed decreased expression of the myofibroblast protein alpha-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.