Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice

Abstract

Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat (HCFD) and the rest from intragastric feeding (iG) of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericelluar fibrosis to AH in 57% (15/26) of the mice, accompanied by inductions of chemokines (Spp1, Cxcl1, Il-17a), progenitor genes (Cd133, Cd24, Nanog, Epcam), PMN infiltration, and clinical features of AH such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce the AH incidence and inductions of progenitor and fibrogenic genes but rather enhances the Il-17a induction and PMN infiltration in some mice. Further, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. In conclusion, these results suggest SPP1 has a protective rather than causal role for experimental AH reproduced in our model.

Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese

“…In contrast, compared with lean mice, HFCD-fed mice gained weight compared with baseline values: 21.5% without alcohol (obese, P = 0.01) and 7.5% with alcohol (OA, P = 0.03). This combination of diet and alcohol use mimicked the common human phenotype and resulted in biochemical and histological changes similar to human ALD as previously reported (24). A detailed lipidomic data for all four groups (mean ± SD) are provided in supplementary Tables 1-7.…”

“…These mice have been used for studies in both diet-induced obesity and alcohol previously (24). Initially, 8-week-old male C57B/6 mice were fed an HFCD containing 20% calories from lard and 1% cholesterol (Dyets Inc., #180724) or chow diet ad libitum for 2 weeks as described previously (23).…”

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

“…Indeed, in addition to IL-4, several other important inflammatory mediators that are associated with neutrophil recruitment, such as OPN and MIP-2, 27,37 were markedly elevated in hepatic iNKT cells after chronicplus-binge ethanol feeding ( Figure 6). Deletion of the OPN gene markedly diminished hepatic neutrophil infiltration and injury in the chronic-plus-binge ethanol feeding model, 37 although this was not observed in a more severe injury model of Tsukamoto-hybrid ethanol feeding 38 or in a mouse model with long-term (7-week) ethanol feeding. 39 Furthermore, the concanavalin-A-induced T-cell hepatitis model was used to demonstrate that release of OPN from iNKT cells led to the subsequent release of MIP-2, both of which aid in the recruitment of neutrophils into the liver and contribute to hepatic injury.…”

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

“…In addition, weekly ethanol binge also caused significant hepatic neutrophil infiltration in chronically intragastric ethanol-fed mice (8). However, the mechanisms by which binge drinking causes neutrophilia are not fully understood.…”