Histone deacetylases as targets in autoimmune and autoinflammatory diseases

Adv Immunol. 2020;147:1-59. doi: 10.1016/bs.ai.2020.06.001. Epub 2020 Jul 15.

Abstract

Reversible lysine acetylation of histones is a key epigenetic regulatory process controlling gene expression. Reversible histone acetylation is mediated by two opposing enzyme families: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Moreover, many non-histone targets of HATs and HDACs are known, suggesting a crucial role for lysine acetylation as a posttranslational modification on the cellular proteome and protein function far beyond chromatin-mediated gene regulation. The HDAC family consists of 18 members and pan-HDAC inhibitors (HDACi) are clinically used for the treatment of certain types of cancer. HDACi or individual HDAC member-deficient (cell lineage-specific) mice have also been tested in a large number of preclinical mouse models for several autoimmune and autoinflammatory diseases and in most cases HDACi treatment results in an attenuation of clinical disease severity. A reduction of disease severity has also been observed in mice lacking certain HDAC members. This indicates a high therapeutic potential of isoform-selective HDACi for immune-mediated diseases. Isoform-selective HDACi and thus targeted inactivation of HDAC isoforms might also overcome the adverse effects of current clinically approved pan-HDACi. This review provides a brief overview about the fundamental function of HDACs as epigenetic regulators, highlights the roles of HDACs beyond chromatin-mediated control of gene expression and summarizes the studies showing the impact of HDAC inhibitors and genetic deficiencies of HDAC members for the outcome of autoimmune and autoinflammatory diseases with a focus on rheumatoid arthritis, inflammatory bowel disease and experimental autoimmune encephalomyelitis (EAE) as an animal model of multiple sclerosis.

Keywords: Animal models; Chromatin/epigenetics; HDACi; Histone deacetylases; Human diseases; Immune cells; Inflammatory bowel disease; Lysine acetylation; Multiple sclerosis; Rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism*
  • Autoimmunity
  • Chromatin / genetics*
  • Epigenesis, Genetic
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histone Deacetylases / therapeutic use
  • Histones / metabolism
  • Humans
  • Inflammation
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / metabolism*
  • Molecular Targeted Therapy
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / metabolism*

Substances

  • Chromatin
  • Histones
  • Histone Deacetylases