Novel insights into double-stranded RNA-mediated immunopathology

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Recognition of self-double-stranded RNA (self-dsRNA) is implicated in autoimmune diseases.
• Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory disease linked to elevated type I interferon levels.
• Mutations in the RNA editing enzyme ADAR1 are found in AGS patients.

Purpose of the Study:

• To elucidate the molecular mechanisms linking self-dsRNA recognition to immunopathology.
• To establish the causal relationship between endogenous dsRNA and type I interferon-driven disease.
• To investigate the role of ADAR1 in preventing pathological responses to self-dsRNA.

Main Methods:

• Utilized novel mouse models with loss-of-function mutations in ADAR1.
• Performed extensive genotype-phenotype analyses in these mouse models.
• Conducted biochemical and genetic analyses to assess ADAR1 function.

Main Results:

• Established a causal link between increased intracellular self-dsRNA and type I interferon-driven immunopathology.
• Demonstrated that MDA5 activation perpetuates type I interferon overproduction.
• Showed that PKR and ZBP1 activation by dsRNA drives pathology via integrated stress response or cell death.
• Identified the cytosolic p150 isoform of ADAR1 as critical for suppressing pathological self-dsRNA responses.

Conclusions:

• ADAR1 is essential for preventing autoimmune pathology triggered by self-dsRNA.
• Dysregulation of self-dsRNA sensing pathways, including MDA5, PKR, and ZBP1, contributes to AGS pathogenesis.
• The p150 isoform of ADAR1 plays a key role in maintaining immune tolerance to self-nucleic acids.