在CNC-bZIP转录因子Nrf2控制表达的矩阵金属蛋白酶在小鼠巨细胞
Abel D Ang1, Sharadha Dayalan Naidu1, Oliver J Read1
1Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, James Arrott Drive, Dundee DD1 9SY, United Kingdom.
Journal of leukocyte biology
|March 4, 2026
概括
转录因子Nrf2调节巨细胞中的矩阵金属蛋白酶 (MMP) 表达,影响肝纤维化. 抑制Keap1激活Nrf2显示出治疗肝纤维化的潜力.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
背景情况:
- 肝纤维化是一种慢性疾病,在晚期没有有效的治疗方法.
- 通过Keap1抑制激活Nrf2,是肝纤维化的有前途的治疗策略.
- 巨细胞在纤维化解消中起着至关重要的作用,它们的功能是治疗策略的关键.
研究的目的:
- 研究Nrf2在慢性肝损伤期间对巨细胞中矩阵金属蛋白酶 (MMP) 表达的调节中的作用.
- 通过调节MMPs来探索Nrf2激活在治疗肝纤维化的治疗潜力.
主要方法:
- 在Nrf2-knockout (Nrf2-ko) 和野生型 (WT) 小鼠肝脏中MMP表达的比较.
- 从Nrf2-ko和Keap1-knockdown (Keap1-kd) 模型中分析骨髓衍生的巨细胞 (BMDMs) 中MMP表达的分析.
- 染色体免疫沉测序 (ChIP-seq) 用于识别Nrf2结合部位.
- 使用TBE-31抑制Keap1.1,对Nrf2进行药理活性化.
主要成果:
- Nrf2-ko小鼠在肝脏中表现出Mmp8,Mmp9,Mmp12和Mmp14的表达受损.
- 在BMDM中Nrf2缺乏导致Mmp8和Mmp12的表达减少,而Keap1 knockdown则增加了它.
- Nrf2直接与Mmp12上游结合,显示出最强的表达反应.
- 药理上的Nrf2激活在BMDM和小鼠肝脏中调节了MMP表达.
结论:
- Nrf2是巨细胞中MMP表达和活性的关键调节者.
- 在巨细胞中Nrf2介导的MMPs调节代表了肝纤维化的新机制.
- 通过抑制Keap1来准Nrf2为肝纤维化提供了潜在的治疗途径.
相关概念视频
NF-κB-dependent Signaling Pathway
10.2K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
10.2K
Role of Matrix Metalloproteases in Degradation of ECM
3.6K
Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult...
3.6K
Master Transcription Regulators
7.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.9K
Co-activators and Co-repressors
8.8K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
8.8K
MAPK Signaling Cascades
8.9K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.9K
Regulation of Nuclear Protein Sorting
3.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.4K


