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

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.

Histone Deacetylation Inhibitors as Therapy Concept in Sepsis

“…A similar protective role was shown with the HDACi TSA [76]. In LPS-dependent endotoxemia, acute lung injury and inflammation were reduced after the application of TSA [77]. This protective role was also evident in bone-marrow-derived macrophages (BMDM) by blocking DNA fragmentation, and reduced expression of pro-apoptotic genes [77].…”

“…In LPS-dependent endotoxemia, acute lung injury and inflammation were reduced after the application of TSA [77]. This protective role was also evident in bone-marrow-derived macrophages (BMDM) by blocking DNA fragmentation, and reduced expression of pro-apoptotic genes [77]. In this cell type, TSA enhances LPS-dependent Cox-2, Cxcl2, and Ifit2 expression, whereas it blocks the expression of the LPS target genes, Ccl2, Ccl7, and Edn1 [57].…”

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

“…Several reports suggest that Hsp90 and HDACs are involved in the pyroptosis of tumor cells and tumor-associated inflammation [40][41][42][43][44][45]. Although the pro-tumorigenic and anti-tumorigenic effects of pyroptosis have been reported in various types of cancers, gasdermin E (GSDME)-mediated pyroptosis might result in normal tissue toxicity after chemotherapy [46][47][48][49][50].…”

Low shear stress regulates vascular endothelial cell pyroptosis through miR‐181b‐5p/STAT‐3 axis

“…As one of the pathologic factors of AS-related diseases, there may be some intrinsic link between cell pyroptosis and STAT-3 (Samanta et al, 2018). STAT-3, one of the important members of the STAT family, is responsible for transmitting the signal of activated serious receptors to the nucleus and can transduce a large number of signals in the immune response (Chen et al, 2019).…”