Altered RNA Editing in Atopic Dermatitis Highlights the Role of Double-Stranded RNA for Immune Surveillance

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Atopic dermatitis (AD) involves dysregulated type 1 interferon (IFN) responses alongside type 2 inflammation.
• The underlying pathophysiology of this IFN dysregulation in AD remains largely unknown.
• Adenosine-to-inosine RNA editing is crucial for immune regulation by modulating double-stranded RNA recognition and subsequent IFN activation.

Purpose of the Study:

• To investigate global adenosine-to-inosine RNA editing levels in atopic dermatitis.
• To elucidate the role of altered RNA editing in the pathophysiology of AD.
• To determine if altered RNA editing is specific to AD compared to other IFN-activated autoimmune diseases.

Main Methods:

• Analysis of three RNA-sequencing datasets from AD skin samples.
• Quantification of global adenosine-to-inosine RNA editing across different genomic regions (Alu repeats, coding genes, pre-mRNA loci).
• Comparison of RNA editing profiles in AD with those in systemic lupus erythematosus and systemic sclerosis.

Main Results:

• Significantly reduced global adenosine-to-inosine RNA editing was detected in AD skin samples.
• This reduction affected Alu repeats, coding genes, and specific pre-mRNA loci targeted by MDA5.
• IFN signature genes were upregulated in AD, while global editing remained unchanged in systemic lupus erythematosus and systemic sclerosis despite IFN activation.

Conclusions:

• Altered adenosine-to-inosine RNA editing, leading to impaired innate immune response, is implicated in the pathogenesis of atopic dermatitis.
• This finding may have relevance for understanding the pathogenesis of other autoimmune and inflammatory diseases.
• The study highlights a potential novel mechanism contributing to AD pathophysiology.