IRAKM and MINCLE in ALD

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ABSTRACT A pivotal stage of the ALD progression is the development of hepatic inflammation, which substantially increases the risk for fibrosis, cirrhosis and cancer. Despite the recent surge in the use of immunomodulatory biologics for other inflammatory diseases, corticosteroids remain the only therapeutic for hepatic inflammation, underscoring a major unmet clinical need. While evidence indicates that a combination of ethanol-induced hepatocyte cell death and elevated circulating endotoxin drives hepatic inflammation in ALD, a major question arising is how the chronic low grade inflammation is initiated and amplified in the progression of ALD. We reported that low-dose endotoxin induces the expression of Mincle, a member of the C-type lectin receptor family that acts as a sensor for cell death, via the IRAKM-dependent TLR4 signaling in hepatic macrophages. Mincle detects components released by dead hepatocytes and activates inflammasomes and IL-1β production, serving as a critical link between cell death and inflammation in murine models of ALD. Recently, we found serum concentrations of β- glucosylceramide (GluCer), a Mincle ligand released by dying hepatocytes, are increased by ethanol feeding in mice and highly elevated in sera from patients with AH. GluCer concentrations were positively correlated with disease severity in patients, suggesting that GluCer may be a major Mincle ligand driving hepatic inflammation and fibrosis in ALD. Intriguingly, Mincle activation leads to a non-lytic form of IL-1β secretion from hepatic macrophages and hepatic stellate cells (HSCs) via a novel GSDMD-mediated biogenesis and release of small extracellular vesicles (sEVs). The non-lytic IL-1β secretion spares hepatic macrophages from pyroptosis, allowing them to continue amplifying the inflammatory response. Importantly, our preliminary data highlight a critical pathogenic role for IL-1β containing sEVs in potentiating ethanol-induced liver injury in mice. Mechanistically, we found that IL-1β induced the expression of SAA in hepatocytes, which in turn activated caspase3-GSDME-mediated pyroptosis. Hepatocyte pyroptosis releases the danger signal HMGB1, which can further activate caspase 1 and 11-dependent GSDMD-cleavage in neighboring hepatocytes, amplifying hepatocyte injury. This escalation of injury not only impairs liver function but likely leads to further release of GluCer, amplifying macrophage inflammatory responses. Importantly, our preliminary data reveal that GluCer also activated HSCs, enhancing collagen deposition and aggravating liver fibrosis. By dissecting the GluCer- Mincle-GSDMD-IL-1β-sEV cascade, this application will evaluate strategies and identify therapeutic targets to interrupt this positive feed forward loop that amplifies the early stage hepatocyte cell death into debilitating hepatic inflammation and fibrosis.