Blocking the gut-liver IgA axis attenuates macrophage-mediated inflammation and injury in alcohol-associated liver disease.

Abstract

Background: Alcohol-associated liver disease (ALD) is a major cause of morbidity, yet therapies for severe inflammation remain limited.

Objective: We examined whether circulating and hepatic immunoglobulin A (IgA) and hepatic myeloid-cell IgA binding are associated with interleukin-1 beta (IL-1β)-linked inflammation and hepatocyte injury in ALD.

Design: This single-centre cross-sectional study enrolled consecutive adults with ALD (n=276), chronic hepatitis B (CHB; n=177) and healthy controls (n=20). A clinically indicated liver-biopsy subcohort underwent flow cytometry, immunohistochemistry and real-time quantitative PCR. Mice received 16-day chronic-plus-binge ethanol feeding±fingolimod (FTY720; 1 mg/kg/day). CD14⁺ monocytes were stimulated on plate-bound secretory IgA (sIgA)±lipopolysaccharide (LPS) and conditioned media were applied to Huh7 cells.

Results: Serum IgA was higher in ALD (median 323-412 mg/dL) than in healthy/CHB (194/211 mg/dL; p<0.001) and correlated with hepatic IgA+area (ρ=0.680, p<0.001). Serum IgA correlated with CD68-normalised IL1B transcripts (ρ=0.383, p=0.008), while hepatic CD14⁺ cells from ALD samples showed greater IgA binding than those from CHB samples (p<0.05). In mice, serum IgA correlated with IgA-bound macrophage frequency (n=16, ρ=0.844, p<0.001). FTY720 reduced serum IgA (p<0.01), IgA-bound macrophages (p<0.001) and Cd68-normalised Il1b transcripts (p<0.01), and attenuated ethanol-induced liver injury (alanine aminotransferase/aspartate aminotransferase; p<0.05). Spatial transcriptomics suggested attenuation in monocyte-derived macrophage-enriched regions and IL-1-linked programmes with FTY720. sIgA+LPS monocyte supernatants contained higher tumour necrosis factor-α/IL-1β than LPS alone (Δ+280/+798 pg/mL, p<0.01) and increased Huh7-cell apoptosis (Δ+2.96% p; p<0.01).

Conclusion: IgA binding to hepatic myeloid cells is associated with interleukin (IL)-1-linked inflammation in ALD, and in ethanol-fed mice pharmacologic modulation of immune-cell trafficking was accompanied by reduced IgA-bound hepatic myeloid cells and attenuated IL-1-related inflammation.