Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease

Area of Science:

• Immunology
• Hepatology
• Cell Biology

Background:

• Mucosal-associated invariant T cells (MAITs) are significantly depleted in alcohol-associated liver disease (ALD).
• The precise mechanisms driving MAIT cell reduction in ALD remain unclear.
• This study investigates the drivers and clinical implications of MAIT cell loss in ALD.

Purpose of the Study:

• To elucidate the mechanisms behind MAIT cell depletion in ALD.
• To assess the clinical significance of MAIT cell loss and pyroptosis in ALD patients.
• To explore potential triggers for MAIT cell pyroptosis in the context of ALD.

Main Methods:

• Evaluated pyroptotic MAIT cells in a cohort of 41 alcohol-associated liver cirrhosis (ALC) patients and 21 with ALC and severe alcoholic hepatitis (ALC + SAH).
• Assessed MAIT cell frequencies, activation markers, and markers of intestinal damage and microbial translocation.
• Investigated MAIT cell pyroptosis in vitro using Escherichia coli stimulation and bilirubin exposure, and examined the effect of IL-18 signaling blockade.

Main Results:

• MAIT cells were decreased, hyperactivated, and exhibited pyroptosis in ALD patients, with increased pyroptosis correlating with disease severity.
• Pyroptotic MAIT cell frequencies were negatively associated with total MAIT cells but positively correlated with MAIT activation and markers of microbial translocation.
• In vitro studies showed MAITs undergo activation and pyroptosis upon stimulation with E. coli or bilirubin, which was reduced by blocking IL-18 signaling.

Conclusions:

• MAIT cell loss in ALD is partly mediated by pyroptosis, directly linked to disease severity.
• Increased pyroptosis may result from inflammatory responses to microbial translocation or direct bilirubin effects.
• These findings highlight pyroptosis as a key mechanism in ALD-associated MAIT cell deficiency.