Other
12 Authors
- Li X,
- Welch N,
- McMullen MR,
- Zhang Q,
- Dasarathy J,
- Zhang R,
- Dasarathy S,
- Nagy LE,
- Wang H,
- Bulek K,
- Liu W,
- Wu X
| First Author | Zhang Q | Year | 2023 |
| Journal | Hepatol Commun | Volume | 7 |
| Issue | 5 | PubMed ID | 37185170 |
| Mgi Jnum | J:359529 | Mgi Id | MGI:7787261 |
| Doi | 10.1097/HC9.0000000000000114 | Citation | Zhang Q, et al. (2023) Mincle-GSDMD-mediated release of IL-1beta small extracellular vesicles from hepatic macrophages in ethanol-induced liver injury. Hepatol Commun 7(5) |
| abstractText | BACKGROUND: Macrophage-inducible C-type lectin (Mincle) is expressed on hepatic macrophages and senses ethanol (EtOH)-induced danger signals released from dying hepatocytes and promotes IL-1beta production. However, it remains unclear what and how EtOH-induced Mincle ligands activate downstream signaling events to mediate IL-1beta release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating beta-glucosylceramide (beta-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which beta-GluCer engages Mincle on hepatic macrophages to release IL-1beta in the absence of cell death and exacerbates ALD. METHOD AND RESULTS: Concentrations of beta-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of hepatic macrophages with lipopolysaccharide and beta-GluCer induced formation of a Mincle and Gsdmd-dependent secretory complex containing chaperoned full-length gasdermin D (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1beta and components of the Caspase 8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEVs). Gao-binge EtOH exposure to wild-type, but not Mincle-/- and Gsdmd-/-, mice increased release of IL-1beta-containing sEVs from liver explant cultures. Myeloid-specific deletion of Gsdmd similarly decreased the formation of sEVs by liver explant cultures and protected mice from EtOH-induced liver injury. sEVs collected from EtOH-fed wild-type, but not Gsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge EtOH-induced liver injury. CONCLUSION: beta-GluCer functions as a danger-associated molecular pattern activating Mincle-dependent gasdermin D-mediated formation and release of IL-1beta-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD. |
