Min Gu Kim, Kwon Yong Tak, Deok Hwa Seo, Gil Won Lee, Sung Woo Cho, Mi Hyun Kwon, Sung Hak Lee, Eui Soo Han, Jae Yong Ryu, Hee Sun Cho, Keung Mo Yang, Ji Won Han, Jeong Won Jang, Ki Young Choi, Pil Soo Sung
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.
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.