Plasma‐Driven Monocyte Dysfunction Drives Disease Progression in Alcohol‐Related Acute‐on‐Chronic Liver Failure

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is associated with immune dysregulation, characterized by simultaneous inflammation and immune suppression. Alcohol-related ACLF (A-ACLF) has particularly high mortality, yet the role of monocyte dysfunction and plasma-derived inflammatory mediators remains poorly understood. METHODS: A prospective study was conducted from July 2019 to May 2020, recruiting A-ACLF patients and healthy controls. Monocyte phenotyping and serum immune markers (sCD163, sCD25, ferritin, and IgG immune complexes) were measured. Ex vivo plasma priming experiments were performed on healthy monocytes, and cytokine production was measured. RESULTS: A-ACLF patients (n = 25, median [min-max] age: 42 [23-64] years, 24 males) showed higher proportions (12.5 [3.47-41.8] vs. 2.98 [0.62-8.89]) and counts of monocytes (counts/μL: 229 [48-1505] vs. 82 [22-250]), with increased classical and reduced patrolling monocyte subsets correlating with higher MELD scores (r = 0.48, p = 0.05) and poor outcomes. A-ACLF monocytes showed increased Fc receptor expression (CD64 MFI: 4648 [2214-7819] vs. 1834 [168-3221]), suggesting monocyte hyperactivation and responsiveness to immune complexes, and lower HLA-DR expression (MFI 444 [133-1147] vs. 916 [451-2067]), indicating immune exhaustion. Increased expression of the liver-homing receptor CCR2 was noted in classical monocytes. Healthy human peripheral monocytes cultured with A-ACLF plasma showed upregulated CCR5 and downregulated CD14, suggesting effects on monocyte trafficking and differentiation. Monocytes primed with A-ACLF plasma secreted higher TNF-α, IL-1β, IL-12, and G-CSF, indicating plasma-driven inflammation. CONCLUSION: Our findings reveal monocyte dysfunction and plasma-induced immune alterations as key contributors to A-ACLF pathogenesis and prognosis. Targeting plasma-derived inflammatory mediators may offer novel therapeutic strategies.