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#apaperaday: Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases

In preparation for my lecture at the Italfarmaco symposium at the Myologie meeting next week I’m reading up on HDAC inhibitors. Today with a review paper by Gatla et al in @IJMS_MDPI from 2019 DOI: 10.3390/ijms20051110

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract each other. HATs add acetyl groups to chromatin, while HDACs remove them. The latter causes the chromatin to be more dense, and reduced expression of genes in that region of the chromosomes.

There are different classes of HDACs, some are expressed only in the nucleus, others in both nucleus and cytoplasm, some in the cytoplasm and some even in the mitochondria. HDAC inhibitors counteract HDACs leading to increased expression of these genes.

Authors outline the different ways HDAC inhibitors are used and tested in trials. HDAC inhibitors have been especially studied for the treatment of hematological cancers, as these cells are very sensitive while non-malignant cells tolerate HDAC inhibitors very well and survive.

HDAC inhibitors can also reduce production of cytokines & chemokines, factors involved in e.g. inflammation. Givinostat can reduce the production of pro-inflammatory cytokines such as IL-1beta and IL-6, which indirectly also reduced levels of my least favorite protein: NFkB

The paper did not consider the Duchenne angle yet because it was written in 2019, but obviously inflammation is an issue in Duchenne muscle and reduction of inflammation is expected to have a therapeutic effect.

HDAC inhibitors can also reduce production of chemokines, which can e.g. attract macrophages to damaged tissue. For chronic diseases, this can result in a disbalance of pro- and anti-inflammatory macrophages. Also here this likely will be beneficial for Duchenne muscles

Authors also outline use for viral infections where counterintuitively the HDAC inhibition is beneficial because it activates latent viruses. This has as a benefit that the infected cells are recognized by anti-viral treatments, while they are not when viruses are latent.

HDAC inhibition has also shown potential in trials for the treatment of cardiovascular diseases, relevant for Duchenne: anti-fibrotic effects. For now, the effect on heart pathology by givinostat has not been evaluated, so we will have to wait and see.

The review goes into more depth for different cytokines and chemokines and ongoing trials for other diseases, and also outlines HDAC use in autoimmune and kidney diseases. If you are interested, read the paper. For the Duchenne angle, I focused on inflammation and heart.