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Journal Article
FRA1
2022
Overview
Filaggrin (FLG), an essential structural protein for skin barrier function, is downregulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the −343/+25 of the FLG promoter was necessary for TNFα + IFNγ–induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ–induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene–induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.
Publisher
National Academy of Sciences
Subject
/ Animals
/ Filaggrin Proteins - genetics
/ Filaggrin Proteins - metabolism
/ Histone Deacetylase 1 - genetics
/ Histone Deacetylase 1 - metabolism
/ Interferon-gamma - pharmacology
/ Keratinocytes - drug effects
/ Mice
/ Multiprotein Complexes - genetics
/ Multiprotein Complexes - metabolism
/ Proto-Oncogene Proteins c-fos - genetics
/ Proto-Oncogene Proteins c-fos - metabolism
/ Proto-Oncogene Proteins c-jun - genetics
/ Proto-Oncogene Proteins c-jun - metabolism
/ Skin
