DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling

The International Journal of Biochemistry & Cell Biology
Saheli SamantaJohnson Rajasingh

Abstract

Acute lung injury (ALI) is a common complication of sepsis that often leads to fatal lung disease without effective therapies. It is known that bone marrow derived macrophages are important in resolving the inflammation and maintaining tissue homeostasis. Here, we hypothesize that treatment in combination of DNA methyl transferase inhibitor (DNMTi) 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) mitigates the inflammation induced pyroptosis and apoptosis during endotoxemia induced ALI. To test this hypothesis, the mice challenged with a sublethal dose of LPS followed by one-hour post-treatment with a single dose of Aza and TSA intraperitoneally showed a substantial attenuation of apoptosis and inflammation. Importantly, we observed significant changes in the mitochondrial membrane structure, and lower levels of DNA fragmentation, reduced expression of apoptotic and pyroptotic genes both transcriptionally and translationally in LPS induced BMDMs treated by a combination of Aza and TSA than in LPS-induced BMDMs treated with either drug alone. The protection was mediated by an inhibition of JNK-ERK and STAT3-JMJD3 activated pathways. Thus, targeting these important signaling pathways with...Continue Reading

Citations

Jun 9, 2020·Journal of Cellular Physiology·Xiangshan XuYuanzhe Jin
Jan 19, 2019·International Journal of Molecular Sciences·Andreas von Knethen, Bernhard Brüne
Nov 30, 2020·Mechanisms of Ageing and Development·Covadonga HuidobroGuillermo M Albaiceta
Feb 18, 2021·Expert Review of Clinical Immunology·Emily da Silva CórneoFelipe Dal-Pizzol
Feb 23, 2021·Frontiers in Pharmacology·Bohao LiuQing Geng
Jun 9, 2021·Reproductive Sciences·Dan LiYeling Wang
Jul 30, 2021·Frontiers in Medicine·Renata Brito Falcão-HolandaReinaldo Salomão

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