Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy.

Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e.

Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration.

Background & Aims: Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver.

Endothelial autophagy is not required for liver regeneration after partial hepatectomy in mice with fatty liver.

Background & Aims: Patients with non-alcoholic fatty liver disease (NAFLD) have impaired liver regeneration. Liver endothelial cells play a key role in liver regeneration. In non-alcoholic steatohepatitis (NASH), liver endothelial cells display a defect in autophagy, contributing to NASH progression.

Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma.

Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach.

MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming.

Recent data have shown that liver fibrosis can regress even at later stages of cirrhosis and shifting the immune response from pro-inflammatory towards a resolutive profile is considered as a promising option. The immune regulatory networks that govern the shift of the inflammatory phenotype and thus potential reversal of liver fibrosis are lesser known. Here we show that in precision-cut human liver slices obtained from patients with end-stage fibrosis and in mouse models, inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches, limits fibrosis progression and even regresses fibrosis, following chronic toxic- or non-alcoholic steatohepatitis (NASH)-induced liver injury.

Targeting cell-intrinsic metabolism for antifibrotic therapy.

In recent years, there have been major advances in our understanding of the mechanisms underlying fibrosis progression and regression, and how coordinated interactions between parenchymal and non-parenchymal cells impact on the fibrogenic process. Recent studies have highlighted that metabolic reprogramming of parenchymal cells, immune cells (immunometabolism) and hepatic stellate cells is required to support the energetic and anabolic demands of phenotypic changes and effector functions. In this review, we summarise how targeting cell-intrinsic metabolic modifications of the main fibrogenic cell actors may impact on fibrosis progression and we discuss the antifibrogenic potential of metabolically targeted interventions.

LC3-associated phagocytosis in myeloid cells, a fireman that restrains inflammation and liver fibrosis, via immunoreceptor inhibitory signaling.

Control of systemic and hepatic inflammation, in particular originating from monocytes/macrophages, is crucial to prevent liver fibrosis and its progression to end-stage cirrhosis. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that shifts the monocyte/macrophage phenotype to an anti-inflammatory phenotype. In a recent study, we uncovered LAP as a protective mechanism against inflammation-driven liver fibrosis and systemic inflammation in the context of cirrhosis.

LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling.

Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects.

[Emergence of 3D human fatty liver models engineered in the laboratory].

Organoids offer an elegant approach to model human diseases and test new drugs. Nonalcoholic fatty liver disease (NAFLD) whose incidence has dramatically increased in recent years with the rise of obesity, is defined by triglyceride accumulation in hepatocytes, inflammation, liver injury, and progression to fibrosis. There is currently no approved therapy but many pathways are being explored.

The aged liver: Beyond cellular senescence.

The aging of the population, the increased prevalence of chronic liver diseases in elderly and the need to broaden the list of potential liver donors enjoin us to better understand what is an aged liver. In this review, we provide a brief introduction to cellular senescence, revisit the main morphological and functional modifications of the liver induced by aging, particularly concerning metabolism, immune response and regeneration, and try to elude some of the signalling pathways responsible for these modifications. Finally, we discuss the clinical consequences of aging on chronic liver diseases and the implications of older age for donors and recipients in liver transplantation.

Age and liver transplantation.

The average age of liver transplant donors and recipients has increased over the years. Independent of the cause of liver disease, older candidates have more comorbidities, higher waitlist mortality and higher post-transplant mortality than younger patients. However, transplant benefit may be similar in older and younger recipients, provided older recipients are carefully selected.

The impact of steatosis on liver regeneration.

Alcoholic and non-alcoholic fatty liver diseases are the leading causes of cirrhosis in Western countries. These chronic liver diseases share common pathological features ranging from steatosis to steatohepatitis. Fatty liver is associated with primary liver graft dysfunction, a higher incidence of complications/mortality after surgery, in correlation with impaired liver regeneration.