Annexin A1 (AnxA1) is an important effector in the resolution of inflammation which is involved in modulating hepatic inflammation in nonalcoholic steatohepatitis (NASH). In this study we have investigated the possible effects of treatment with AnxA1 for counteracting the progression of experimental NASH. NASH was induced in C57BL/6 mice by feeding methionine-choline deficient (MCD) or Western diets and the animals were treated for 4-6 weeks with human recombinant AnxA1 (hrAnxA1; 1µg, daily IP) or saline once NASH was established. In both experimental models, treatment with hrAnxA1 improved parenchymal injury and lobular inflammation without interfering with the extension of steatosis. Furthermore, administration of hrAnxA1 significantly attenuated the hepatic expression of α1-procollagen and TGF-ß1 and reduced collagen deposition, as evaluated by collagen Sirius Red staining. Flow cytometry and immunohistochemistry showed that hrAnxA1 did not affect the liver recruitment of macrophages, but strongly interfered with the formation of crown-like macrophage aggregates and reduced their capacity of producing pro-fibrogenic mediators like osteopontin (OPN) and galectin-3 (Gal-3). This effect was related to an interference with the acquisition of a specific macrophage phenotype characterized by the expression of the Triggering Receptor Expressed on Myeloid cells 2 (TREM-2), CD9 and CD206, previously associated with NASH evolution to cirrhosis. Collectively, these results indicate that, beside ameliorating hepatic inflammation, AnxA1 is specifically effective in preventing NASH-associated fibrosis by interfering with macrophage pro-fibrogenic features. Such a novel function of AnxA1 gives the rational for the development of AnxA1 analogues for the therapeutic control of NASH evolution.
The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/-) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.
Background and Aims: Metabolic syndrome (MetS) is a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The prevalence of MetS parallels the rise of obesity rate reaching pandemic proportions due to the increased consumption of high-calories-high-fat-high-carbohydrates low-fibers diet associated with a sedentary lifestyle. MetS is associated with a plethora of comorbidities as non-alcoholic fatty liver disease (NAFLD). Noteworthy, NAFLD is considered the hepatic manifestation of MetS, and it can further progress to non-alcoholic steatohepatitis (NASH) that, in its turn, can evolve to cirrhosis and hepatocellular carcinoma (HCC). Despite the clinical relevance of NAFLD/NASH, however, effective therapy is still lacking. Lifestyle changes, including diet and physical activity, are so far the most effective interventions in NAFLD. Referring to nutritional approaches, however, there is not a definitive agreement concerning the dietary regimen to introduce into clinical practice. In this study, we investigated the capacity of a cholesterol-free ketogenic diet (KD) to improve pathological parameters associated with experimental MetS. Methods: MetS was induced in C57BL/6 mice by feeding with a cholesterol-enriched western diet (WD) up to 16 weeks followed by the switching to KD for further 8 weeks. WD and KD were chemical characterized through GC and SD-PAGE analysis. Results: KD administration in MetS mice significantly improved the liver pathological manifestations by lowering the gene expression of pro-inflammatory/fibrogenetic markers such as CCl2, IL-12, CD11b, OPN, Gal-3, TGF-β and α1-procollagen. Furthermore, KD feeding decreased the hepatic content of triglycerides and the hepatocellular damage, as testified by the reduction in ALT release. These observations were further supported by the histological analyses that revealed a significant amelioration in the extent of steatosis, necro-inflammation, and collagen fibers deposition, as confirmed by the Sirius-red staining in KD-fed mice. Interestingly, KD reduced the splenomegaly observed in WD-fed mice suggesting a reduction in chronic systemic inflammation. Finally, KD feeding ameliorated WD-induced muscle atrophy as confirmed by the recovery of the gastrocnemius mass. Microbiota analyses are ongoing. Conclusion: Altogether these results suggest that cholesterol-free ketogenic diet administration might represent a potential therapeutic strategy for MetS.
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