Role of Aldose Reductase in LPS‐inducible Intrahepatic Immune Infiltration and Inflammation

Aldose reductase (AR) is the rate‐limiting enzyme of the polyol pathway that converts glucose to sorbitol, which is further metabolized to fructose. AR has been widely investigated in pathogenesis of diabetic complications, cardiovascular disorders and cancer. Previous studies show that activation of AR is involved in glucose‐induced hepatitis in mice, hepatitis in rats and human autoimmune hepatitis. Recent findings demonstrate that AR is involved in inflammatory hepatic ischemia‐reperfusion injury. The gut‐liver axis is known to be involved in the development of both alcoholic and non‐alcoholic liver diseases. Gut permeability releases endotoxin (lipopolysaccharide, LPS) into circulation and then triggers inflammation. Inflammatory responses are among the most critical pathological processes associated with liver injury. This study investigated the role of AR in intrahepatic immune infiltration/activation and inflammation using mouse models and human specimens from patient with inflammatory liver disease. Wild type (WT, C57BL/6) and aldose reductase knockout mice (ARKO, AKR1B3−/−) were subjected to stimulation with or without LPS (2.0mg/kg) through intraperitoneal injection. Liver histology (H&E staining), intrahepatic immune cell markers (F4/80, chloroacetate esterase stain ) and apoptosis (TUNEL) were examined. Intrahepatic immune cells were isolated from mouse livers and analyzed by flow cytometry using immunofluorescence antibodies: anti‐CD11b, anti‐F4/80, anti‐ly6G and anti‐ly6C. The expression levels of AR in hepatitis patient livers were evaluated by real‐time PCR. Proinflammatory cytokines (TNFα, IL‐1β, IL‐6) and chemokines (CXCL2 and MCP‐1/CCL2) were significantly upregulated in WT mice exposed to LPS. The genetic deletion of AR greatly attenuated LPS‐induced cytokines/chemokines. LPS resulted in the infiltration of circulating neutrophils and monocytes into the liver and increased CD11b + Kuffer subsets in WT mice. The lack of AR in ARKO mice was associated with decreased populations of neutrophils, monocytes and CD11b + Kuffer cells. Specifically, administration of LPS increased neutrophils (F4/80 − /CD11b + /Ly6G + /SSC int ) by 5 fold in WT mice and AR deficiency reduced this to 3 fold; LPS elevated intrahepatic inflammatory monocytes (F4/80 − /CD11b + /ly6C hi ) by 2 fold in WT mice and AR deficiency reduced this to 1 fold. LPS increased the CD11b + Kupffer cell subset (F4/80 + CD11b + ) by 2 fold in WT mice and AR deficiency decreased this to 1 fold. Hepatic AR expression was significantly upregulated by 2 fold in patients with inflammatory liver disease. Taken together, our data show that AR is a key mediator of hepatic inflammation in response to endotoxin in mice. The upregulation of hepatic AR in patients with hepatitis emphasize the relevance of AR in human liver diseases associated with inflammation. The data also suggest that AR may be a novel therapeutic target for inflammatory hepatic injury. Support or Funding Information NIH‐NIEHS, NIH‐NIAAA, DOD, VA, and UofL‐IPIBS This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .