Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease

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.

Keywords: ILC1; NAFLD; NASH; NK cells; inflammation; liver.

Figure 1

Spectrum of hepatic abnormalities in NAFLD. During obesity, liver complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. NASH, non-alcoholic steatohepatitis; HCC, hepatocellular carcinoma.

Figure 2

Type 1 ILC during obesity-induced liver inflammation. Obesity is associated with adipose tissue dysfunction, increased gut permeability and dysbiosis. These alterations are responsible for the release of bacterial products, the increase in endotoxin levels, the afflux of free fatty acids in the portal circulation as well the increase of de novo lipogenesis. These extra hepatic actors participate in the establishment of hepatic low grade inflammation. This leads to the activation of innate immune cells (group 1 ILC, dendritic cells, macrophages) and maintain the process of hepatic inflammation, via the production of inflammatory cytokines. All these events lead to a vicious cycle that aggravates liver injury, increases inflammation and thus promotes progression to more severe stages of the disease. Rae-1, retinoic acid early inductible−1; TRAIL, TNF-related apoptosis-inducing ligand; PPAR, peroxisome proliferator-activated receptor; Cpt1a, Carnitine Palmitoyltransferase 1a; NEFA, Non esterified fatty acid; FFA, Free fatty Acid; ILC, Innate Lymphoid Cells.