Background: Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. Objective: The aim of this study was to investigate the role of miR-146a in skin inflammation in AD.
Results: We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-γinducible and ADassociated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1β. In a mouse model of AD, miR-146adeficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-γ CCL5, CCL8, and UBD in the skin, and IFN-γ IL-1β, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146amediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain- ontaining protein 10 and IL-1 receptorassociated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a.
Conclusion: Our data demonstrate that miR-146a controls nuclear factor kappa Bdependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.
- atopic eczema
- gene therapy
- noncoding RNA
ASJC Scopus subject areas
- Immunology and Allergy