DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling. (September 2018)

• Record Type: Journal Article
• Authors: Samanta, Saheli; Zhou, Zhigang; Rajasingh, Sheeja; Panda, Arunima; Sampath, Venkatesh; Rajasingh, Johnson
• Is Part Of: International journal of biochemistry & cell biology. Volume 102(2018)
• Page Start: 117
• Page End: 127
• Publication Date: 2018-09
• Subjects: Epigenetic modifiers -- Acute lung injury -- Inflammation -- STAT3 -- JMJD3 -- Pyroptosis -- Apoptosis; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2018.07.002
• Languages: English
• ISSNs: 1357-2725

Abstract

Graphical abstract: Proposed molecular mechanisms of the combination Aza and TSA treatment mediated protection on endotoxemia induced macrophage apoptosis and pyroptosis . In bone maroow derived macrophages (BMDMs), LPS activates JMJD3- STAT3 signaling pathway by MEK/MAP kinases. Moreover, the increase of JMJD3 by LPS induces pro-inflammatory cytokines, and result in apoptosis of the cells. However, epigenetic modifiers Aza and TSA, which inhibits the activity of MAPK, JMJD3-STAT3 signaling and restores mitochondrial membrane integrity, and thereby reverses the apoptosis and pyroptosis of BMDMs induced by LPS. Highlights: Aza and TSA reduces the LPS induced mitochondrial DNA fragmentation, apoptotic and pyroptotic genes in macrophages. LPS induced inflammatory pathway is mainly mediated through the activation of JNK-ERK and STAT3-JMJD3. Treatment with Aza and TSA together abrogate the inflammatory pathway through their epigenetic modification. 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 the combination of Aza and TSA would be a good treatment modality for ALI.