Melatonin ameliorates necrotizing enterocolitis by preventing Th17/Treg imbalance through activation of the AMPK/SIRT1 pathway
| Autor: | Lixin Zhu, Pu-Ping Liang, Congcong Shi, Yao Cai, Dandan Hu, Xin Xiao, Fei Ma, Bowei Chen, Xiaoyan Gao, Hu Hao, Qiuming He, Sitao Li, Junjian Lv, Jialiang Zhou |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.drug_class AMPK/SIRT1 pathway Medicine (miscellaneous) AMP-Activated Protein Kinases Pharmacology Monoclonal antibody T-Lymphocytes Regulatory Flow cytometry Melatonin Mice 03 medical and health sciences 0302 clinical medicine Sirtuin 1 Enterocolitis Necrotizing melatonin necrotizing enterocolitis Th17/Treg imbalance Intestine Small medicine Animals Humans Intestinal Mucosa intestine Pharmacology Toxicology and Pharmaceutics (miscellaneous) medicine.diagnostic_test business.industry Infant Newborn AMPK Hypoxia (medical) medicine.disease In vitro Disease Models Animal 030104 developmental biology Animals Newborn Cell culture 030220 oncology & carcinogenesis Necrotizing enterocolitis Th17 Cells medicine.symptom business hormones hormone substitutes and hormone antagonists Research Paper Signal Transduction medicine.drug |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.45862 |
| Popis: | Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants. Mounting evidence supports the therapeutic effect of melatonin on NEC, although the underlying mechanisms remain unclear. Methods: NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of formula containing enteric bacteria, and then, mice received melatonin, melatonin + recombinant IL-17, melatonin + anti-CD25 monoclonal antibody, melatonin + Ex-527, or melatonin + Compound C treatment. Control mice were left with their dams to breastfeed and vehicle-treated NEC pups were used as controls for treatment. Ileal tissues were collected from mice and analyzed by histopathology, immunoblotting, and flow cytometry. FITC-labeled dextran was administered to all surviving pups to evaluate gut barrier function by fluorometry. We used molecular biology and cell culture approaches to study the related mechanisms in CD4+ T cells from umbilical cord blood. Results: We demonstrated that melatonin treatment ameliorates disease in an NEC mouse model in a manner dependent on improved intestinal Th17/Treg balance. We also showed that melatonin blocks the differentiation of pathogenic Th17 cells and augments the generation of protective Treg cells in vitro. We further demonstrated that the Th17/Treg balance is influenced by melatonin through activation of AMPK in the intestine, in turn promoting SIRT1 activation and stabilization. Conclusions: These results demonstrate that melatonin-induced activation of AMPK/SIRT1 signaling regulates the balance between Th17 and Treg cells and that therapeutic strategies targeting the Th17/Treg balance via the AMPK/SIRT1 pathway might be beneficial for the treatment of NEC. |
| Databáze: | OpenAIRE |
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