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

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.

Automated summary

The study reveals that silencing of HDAC8 and HDAC9 in keratinocytes leads to loss of tolerance to TLR ligands, with MAP2K3 potentially playing a key role in establishing immune tolerance. Proteomic analysis further identifies an association between HDAC8/9 and SSRP1 and SUPT16H, proteins responsible for transcriptional elongation of MAP2K3.