iScience
·
2023
·
IF 5.8
Yixuan Liu,Qi Sun,Chengfei Zhang,Min Ding,Cheng Wang,Qian Zheng,Zhijie Ma,Haojun Xu,Guoren Zhou,Xiaoming Wang,Zhangjun Cheng,Hongping Xia
Summary The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Li Chai,Chaoqun Li,Xuefeng Wang,Yanyang Qin,Hemin Sun,Jie Du,Liu Yang,Dongmei Hu,Jianan Xiong,Zhiyuan Zhao,Rong Gong,Tao Wu,Meng Wu,Meng Nie,Jialin Gao,Jihui Jia,Chengjiang Gao,Wei Zhao,Huan Zhou,Dongwei Kang,Mutian Jia
Perturbation of energy metabolism is an essential feature during infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.
研究领域:
免疫学
·
分子生物学
·
代谢调控
·
先天免疫
·
病毒感染
·
信号转导
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2022
·
IF 9.995
Yi Li,Yu-Chen Li,Xiao-Tian Liu,Lu Zhang,Yi-Hua Chen,Qiong Zhao,Wen Gao,Baolin Liu,Hua Yang,Ping Li
Summary The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1 α (HIF-1 α ) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U- 13 C 6 ] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U- 13 C 5 ] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD + content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.
研究领域:
免疫学
·
代谢
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
TRENDS IN BIOTECHNOLOGY
·
2025
·
IF 14.9
An Lao,Weiqi Li,Yiting Sun,Yuting Cao,Yu Zhuang,Jianyong Wu,Dejian Li,Kaili Lin,Jing Mao,Jiaqiang Liu
Type 2 diabetes (T2D) is characterized by persistent and unresolved tissue inflammation caused by the infiltration and dysregulation of immune cells. Current therapeutics targeting inflammatory immune cells for T2D remain limited. In this study, we analyzed single cell RNA from metabolic organs in T2D, revealing increased macrophage accumulation and a pathogenic macrophage subpopulation defined as NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) + inflammatory and metabolically activated macrophages. To target these inflammatory cells, we developed nanovesicles encapsulating mitochondrial metabolic enzyme-related gene segments [immune-responsive gene 1 (IRG1)-overexpression plasmids] with cell membrane decoration. The nanovesicles functioned as cellular itaconate producers that elegantly circumvented the drug utilization barriers of a classic NLRP3 inhibitor and, as a mitochondria-reprograming system, mitigated fatty acid (FA)-associated metabolic dysfunction. The nanovesicles reversed inflammation, restored metabolic functions, and ameliorated obesity. Therefore, the metabolic and immunomodulatory functions of nanovesicles may offer translational opportunities for the prevention and treatment of T2D.
研究领域:
免疫代谢
·
基因治疗
·
纳米医学
·
糖尿病研究
·
炎症性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）