ADAR1 Prevents Autoinflammatory Processes in the Heart Mediated by IRF7

Area of Science:

• Cardiology
• Molecular Biology
• Immunology

Background:

• ADAR1-mediated RNA editing distinguishes self from non-self RNA, preventing autoimmune responses.
• The specific roles and mechanisms of ADAR1 in cardiomyocytes remain unclear.
• ADAR1 influences cellular processes through RNA editing and potentially editing-independent pathways.

Purpose of the Study:

• To elucidate the function of ADAR1 in cardiomyocytes.
• To differentiate between editing-dependent and editing-independent roles of ADAR1 in the heart.
• To investigate the molecular mechanisms underlying ADAR1's cardiac functions.

Main Methods:

• Utilized various Adar1-mutant mouse models, including those with inactivated enzymatic activity.
• Combined Adar1 mutations with Ifih1 or Irf7 gene inactivation.
• Employed immunofluorescence, Western blot, RNAseq, proteomics, and functional MRI for analysis.

Main Results:

• Adar1 inactivation in cardiomyocytes led to autoinflammatory myocarditis, dilated cardiomyopathy, and heart failure.
• ADAR1 deficiency activated interferon signaling, with IRF7 identified as the key mediator of autoinflammatory responses.
• Inactivation of MDA5 (Ifih1) delayed heart failure but did not prevent lethality, while catalytically inactive ADAR1 in an Ifih1-mutant background showed normal function.

Conclusions:

• Enzymatically active ADAR1 is essential for preventing IRF7-mediated autoinflammatory reactions in the heart triggered by endogenous RNAs.
• ADAR1 possesses critical editing-independent functions vital for long-term cardiac function and survival.