Abstract
Obesity and associated liver diseases (Non Alcoholic Fatty Liver Disease, NAFLD) are a major public health problem with increasing incidence in Western countries (25% of the affected population). These complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades. Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue-resident ILCs, mainly located at epithelial surfaces, are prompt to rapidly react to environmental changes to mount appropriate immune responses. Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. Here, we provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD. We also discuss recent studies that demonstrate the ability of these two subsets to influence tissue-specific metabolism and how their function and homeostasis are affected during metabolic disorders.
Highlights
Non-alcoholic Fatty Liver Disease (NAFLD) has recently become a pathology of interest as its increased prevalence is associated with obesity and metabolic syndrome
We evaluate the potential role of Natural Killer (NK) cells and ILC1 in the pathophysiology of NAFLD
Type 1 Innate lymphoid cells (ILC) represent a major innate cell population in the liver and their ability to respond to various signals and to interact with macrophages allow them to be a credible candidate involved in the development and severity of NAFLD (Figure 2)
Summary
Non-alcoholic Fatty Liver Disease (NAFLD) has recently become a pathology of interest as its increased prevalence is associated with obesity and metabolic syndrome. Among the CD56bright subset in the liver, a rare fraction (2.3%) are Eomes− T-bet+ and expresses CD49a producing high levels of IFN-γ, TNF-α and GM-CSF [67] This small subset of liver CD56bright CD49a+ cells represent a putative human counterpart to mouse hepatic CD49a+ ILC1/tr NK cells. A gene expression pattern of inflammatory markers such as IFN-γ, TNF-α, IL-18, CCL5, CXCL10 are upregulated in the NASH liver of morbidly obese patients compared to lean subjects that could be produced and/or could regulate type 1 ILC behavior [75, 76]. In a murine model of steatohepatitis (methionine and choline deficient diet), IFNγ-producing NK cells polarize macrophages toward M1 and NK cell depletion prevent fibrogenesis [88] In this mouse model, activated liver CD49b+ NK cells are increased whereas liver CD49a+ ILC1 are decreased suggesting a finely tuned interplay between these subsets. Type 1 ILC represent a major innate cell population in the liver and their ability to respond to various signals (stressed cells expressing NK receptor ligands, death receptors, IL-12/IL-18 cytokines, CCL5, CXCL10 chemokines. . .) and to interact with macrophages allow them to be a credible candidate involved in the development and severity of NAFLD (Figure 2)
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