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

Autor: Richard L. Gallo, Marc C. Liggins, Tatsuya Dokoshi, George L. Sen, Teruaki Nakatsuji, Yu Sawada, Nikhil Nitin Kulkarni
Rok vydání: 2021
Předmět:
0301 basic medicine
Keratinocytes
medicine.medical_treatment
T-Lymphocytes
MAP Kinase Kinase 3
Transgenic
Epigenesis
Genetic
Mice
0302 clinical medicine
Innate
Cells
Cultured
Skin
Cultured
Imiquimod
Toll-Like Receptors
General Medicine
Cell biology
Cytokine
medicine.anatomical_structure
Infectious Diseases
medicine.symptom
Keratinocyte
Staphylococcus aureus
Ultraviolet Rays
T cell
Cells
1.1 Normal biological development and functioning
Immunology
Inflammation
Mice
Transgenic
Biology
Article
Histone Deacetylases
Vaccine Related
03 medical and health sciences
Genetic
Clinical Research
Underpinning research
Biodefense
medicine
Immune Tolerance
Genetics
Gene silencing
Animals
Humans
Innate immune system
Prevention
Inflammatory and immune system
Immunity
HDAC8
Dendritic cell
Dendritic Cells
Immunity
Innate
Repressor Proteins
030104 developmental biology
Emerging Infectious Diseases
030215 immunology
Epigenesis
Zdroj: Science immunology, vol 6, iss 59
Sci Immunol
Popis: 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.
Databáze: OpenAIRE
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