Research ArticleSKIN INFLAMMATION

Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9

See allHide authors and affiliations

Science Immunology  21 May 2021:
Vol. 6, Issue 59, eabe1935
DOI: 10.1126/sciimmunol.abe1935

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Cutaneous chaos control by HDACs

The skin’s epidermal surface is routinely exposed to a diverse mix of physical, chemical, and microbial stimuli with proinflammatory potential. Epidermal keratinocytes have an innate tendency to tolerate this maelstrom by relying on the histone deacetylases HDAC8 and HDAC9 to restrain signaling pathways that can amplify local inflammation. Sawada et al. used transcriptomic profiling of human keratinocytes activated by poly I:C, a dsRNA mimic, to identify the kinase MAP2K3 as a pivotal target for regulation by HDAC8/9. Inhibition or silencing of HDAC8 or HDAC9 increased expression of MAP2K3 and activation of its downstream target p38MAPK. These findings provide a deeper understanding of how skin inflammation is normally held in check and pinpoint two kinases as potential targets for therapeutic inhibition in inflammatory skin diseases.

Abstract

The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus. These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.

View Full Text

Stay Connected to Science Immunology