Potteti Haranatha R, Venkareddy Lalith K, Noone Patrick M, Ankireddy Aparna, Tamatam Chandramohan R, Mehta Dolly, Tiruppathi Chinnaswamy, Reddy Sekhar P
Departments of Pediatrics, University of Illinois, Chicago, IL 60612, USA.
Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA.
Antioxidants (Basel). 2021 May 26;10(6):847. doi: 10.3390/antiox10060847.
The aberrant regulation of inflammatory gene transcription following oxidant and inflammatory stimuli can culminate in unchecked systemic inflammation leading to organ dysfunction. The Nrf2 transcription factor dampens cellular stress and controls inflammation by upregulating antioxidant gene expression and TNFα-induced Protein 3 (TNFAIP3, aka A20) deubiquitinase by controlling NF-kB signaling dampens tissue inflammation. Here, we report that Nrf2 is required for induction by inflammatory stimuli LPS in monocyte/bone marrow derived macrophages (MDMΦs) but not in lung-macrophages (LDMΦs). LPS-induced A20 expression was significantly lower in MDMΦs and was not restored by antioxidant supplementation. Nrf2 deficiency markedly impaired LPS-stimulated mRNA expression MDMΦs and ChIP assays showed Nrf2 enrichment at the promoter MDMΦs upon LPS stimulation, demonstrating that Nrf2 directly regulates expression. Contrary to MDMΦs, LPS-stimulated expression was not largely impaired in LDMΦs ex vivo and in vivo and ChIP assays showed lack of increased Nrf2 binding at the promoter in LDMΦ following LPS treatment. Collectively, these results demonstrate a crucial role for Nrf2 in optimal transcriptional induction in macrophages by endotoxin, and this regulation occurs in a contextual manner.
在氧化应激和炎症刺激后，炎症基因转录的异常调节可能最终导致不受控制的全身炎症，进而引发器官功能障碍。核因子E2相关因子2（Nrf2）转录因子通过上调抗氧化基因表达以及通过控制核因子κB（NF-κB）信号传导来抑制细胞应激并控制炎症，而NF-κB信号传导可抑制组织炎症，Nrf2还能上调肿瘤坏死因子α诱导蛋白3（TNFAIP3，又名A20）去泛素酶。在此，我们报告，在单核细胞/骨髓来源的巨噬细胞（MDMΦs）中，Nrf2是炎症刺激物脂多糖（LPS）诱导所必需的，但在肺巨噬细胞（LDMΦs）中并非如此。在MDMΦs中，LPS诱导的A20表达显著降低，且抗氧化剂补充不能恢复该表达。Nrf2缺陷显著损害了LPS刺激的MDMΦs中的mRNA表达，染色质免疫沉淀（ChIP）分析显示，LPS刺激后，Nrf2在MDMΦs的启动子处富集，表明Nrf2直接调节其表达。与MDMΦs相反，LPS刺激的LDMΦs在体外和体内的表达并未受到很大损害，ChIP分析显示，LPS处理后，LDMΦs的启动子处Nrf2结合没有增加。总的来说，这些结果证明了Nrf2在内毒素诱导巨噬细胞最佳转录中的关键作用，并且这种调节是以上下文相关的方式发生的。
