Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Abstract

Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. Here, we examined the efficacy of DNA methyl transferase (DNMT) inhibitor Aza (5-Aza 2-deoxycytidine), histone deacetylase (HDAC) inhibitor TSA (Trichostatin A), and combination therapy (Aza+TSA) in protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung histopathological changes, and inflammations. Importantly, these protective effects were due to significant macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in ALI. This finding gives further evidence that the epigenetic treatment has a therapeutic potential for patients with sepsis.

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

“…Inhibition of histone deacetylases (HDACs) regulates the acetylation status of different genes associated with inflammation [5,83] or other diseases, such as cancer [84], CVDs [85], and metabolic homeostasis [86]. In recent years, HDAC inhibitors have demonstrated great potential in serving as a therapeutic treatment for the suppression of inflammation in macrophages.…”

“…Recently, it was shown that 5-Aza 2-deoxycytidine (Aza), a DNMTi and TSA, a total inhibitor for HDACs, have the potential to treat inflammation. The study demonstrated that the combination of Aza+TSA not only decreased the expression of M1 macrophages, but also increased M2 macrophage expression in LPS-induced primary mouse bone marrow-derived macrophages (BMDMs) [13]. …”

“…More specific is the desire to manipulate post-translational modifications of histones and noncoding RNA [3] by using epigenetic modifiers. Recently, studies have shown that using agents that modulate chromatin systems in macrophages are of potential therapeutic value in controlling proinflammatory responses [11–13]. Thus, in an attempt to seek a treatment for inflammation, researchers have directed their attention to identify drugs that epigenetically target macrophages.…”

Epigenetic dysfunctional diseases and therapy for infection and inflammation

“…A single dose of combinatorial administration of Aza+TSA after the onset of acute lung injury (ALI) has been found to significantly attenuate lung vascular hyper permeability and inflammatory lung injury. Moreover, the combinatorial treatment with Aza+TSA reduces inflammation and promotes anti-inflammatory M2 macrophages during ALI [135, 136]. These two studies clearly demonstrated that epigenetic modifiers have a therapeutic potential for patients with sepsis-induced vascular injury and inflammation.…”

Reprogramming of macrophages — new opportunities for therapeutic targeting

“…It will be of great interest to learn, if macrophages stimulated by other stress-signals will respond in a similar fashion to these novel JMJD3 and UTX inhibitors. Further promising support for targeting transcriptional and epigenetic regulation comes from a study using the DNA methyl transferase (DNMT) inhibitor 5-Aza 2-deoxycytidine (Aza) and the HDAC inhibitor Trichostatin A (TSA) to treat murine LPS-induced acute lung injury [61]. Combinatorial treatment with Aza + TSA reduced inflammation and promoted an anti-inflammatory macrophage program.…”