Abstract
Abstract Atopic dermatitis (AD) is a complex and multifactorial skin disease characterized by skin inflammation and intense pruritus. AD is often diagnosed based on symptoms, but a precise diagnosis and treatment are difficult due to various symptoms. This study aimed to develop a safe and effective therapeutic agent and identify a novel therapeutic target for AD. We verified the functions and mechanism of interferon regulatory factor3 (IRF3) as a novel therapeutic target of AD. IRF3, a transcription factor regulating various pro-inflammatory cytokines, including IL-33, was significantly increased in the skin lesions of AD mice and patients with AD. However, deficiency of IRF3 relieved AD symptoms and pathophysiological changes, including skin thickening (the dermis and epidermis thickening), immune cell infiltration, serum immunoglobulins level, and pro-inflammatory cytokines. In damaged AD tissues, IRF3 regulated the expression of cytokeratin 1 (KRT1) and 10 (KRT10). IRF3 also altered the expression of nuclear IL-33 in the epidermis and the extracellular IL-33 in the dermis of AD mouse tissues. In vitroexperiments using human keratinocytes, knockdown or overexpression of IRF3 regulated the nuclear localization and the extracellular release of IL-33. Thus, IRF3 is an essential factor in the onset and exacerbation of AD by inducing skin barrier abnormalities as well as activation of the immune system. Collectively, our studies identify IRF3 as a positive regulator for IL-33, highlighting a novel therapeutic target for AD and suggesting a novel solution for treating intractable dermatitis.
Published Version
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