PDF(Pubmed)
Abstract：
Stefin B (cystatin B) is an inhibitor of lysosomal and nuclear cysteine cathepsins. The gene for stefin B is located on human chromosome 21 and its expression is upregulated in the brains of individuals with Down syndrome. Biallelic loss-of-function mutations in the stefin B gene lead to Unverricht-Lundborg disease-progressive myoclonus epilepsy type 1 (EPM1) in humans. In our past study, we demonstrated that mice lacking stefin B were significantly more sensitive to sepsis induced by lipopolysaccharide (LPS) and secreted higher levels of interleukin 1-β (IL-1β) due to increased inflammasome activation in bone marrow-derived macrophages. Here, we report lower interleukin 1-β processing and caspase-11 expression in bone marrow-derived macrophages prepared from mice that have an additional copy of the stefin B gene. Increased expression of stefin B downregulated mitochondrial reactive oxygen species (ROS) generation and lowered the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in macrophages. We determined higher AMP-activated kinase phosphorylation and downregulation of mTOR activity in stefin B trisomic macrophages-macrophages with increased stefin B expression. Our study showed that increased stefin B expression downregulated mitochondrial ROS generation and increased autophagy. The present work contributes to a better understanding of the role of stefin B in regulation of autophagy and inflammasome activation in macrophages and could help to develop new treatments.
摘要：
StefinB（胱抑素B）是溶酶体和核半胱氨酸组织蛋白酶的抑制剂。StefinB的基因位于人类21号染色体上，其表达在唐氏综合症患者的大脑中上调。StefinB基因的双等位基因功能丧失突变导致人类Unverricht-Lundborg疾病进行性肌阵挛性癫痫1型（EPM1）。在我们过去的研究中，我们证明,缺乏StefinB的小鼠对脂多糖(LPS)诱导的脓毒症明显更敏感,并且由于骨髓源性巨噬细胞的炎性小体激活增加,小鼠分泌的白细胞介素1-β(IL-1β)水平更高.这里,我们报道了白细胞介素1-β加工和caspase-11表达较低的骨髓源性巨噬细胞,这些巨噬细胞由具有额外的stefinB基因拷贝的小鼠制备而成.StefinB的表达增加下调了线粒体活性氧（ROS）的产生，并降低了巨噬细胞中包含NLR家族pyrin结构域3（NLRP3）炎性小体的激活。我们在StefinB三体巨噬细胞-巨噬细胞中确定了更高的AMP激活激酶磷酸化和mTOR活性下调，同时StefinB表达增加。我们的研究表明，StefinB表达的增加下调了线粒体ROS的产生并增加了自噬。目前的工作有助于更好地了解StefinB在调节巨噬细胞自噬和炎性小体激活中的作用，并可能有助于开发新的治疗方法。
