Cleavage-Resistant CYLD Protects Against Autoimmune Hepatitis

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Autoimmune hepatitis (AIH) is an immune-mediated liver disease with poorly understood pathogenic mechanisms.
• AIH can lead to severe liver complications including fibrosis, cirrhosis, and hepatocellular carcinoma.
• Current therapies for AIH are limited by incomplete understanding of disease drivers.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying autoimmune hepatitis (AIH) progression.
• To identify novel therapeutic targets for AIH.
• To investigate the role of cylindromatosis (CYLD) in experimental autoimmune hepatitis (EAH).

Main Methods:

• Utilized a concanavalin A-induced murine model of experimental autoimmune hepatitis (EAH).
• Generated and analyzed mice with macrophage-specific, cleavage-resistant Cyld (CyldD215A/D215A) mutation.
• Investigated the interaction between CYLD, TRIM25, and MEK1/2 signaling pathways in macrophages.
• Assessed the therapeutic potential of MEK1/2 inhibition in EAH.

Main Results:

• Proteolytic cleavage of CYLD at Asp215 was identified as a critical event promoting EAH progression.
• Macrophage-specific CyldD215A/D215A mutant mice showed significant protection from hepatic injury.
• TNFα-induced CYLD cleavage in macrophages enhances alarmin-triggered chemokine production via MEK1/2 activation.
• CYLD and TRIM25 cooperatively regulate MEK1/2 ubiquitination, promoting its activation and subsequent chemokine production.
• Pharmacological MEK1/2 inhibition markedly reduced EAH severity.

Conclusions:

• A novel CYLD-MEK1/2 signaling axis in macrophages plays a crucial role in orchestrating hepatic inflammation in AIH.
• CYLD stability is a key regulator of liver inflammation.
• MEK signaling represents a promising therapeutic target for autoimmune hepatitis.