Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

Abstract

Obesity is a prevalent predisposing factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the developed world. NAFLD spectrum of disease involves progression from steatosis (NAFL), to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Despite clinical and public health significance, current FDA approved therapies for NAFLD are lacking in part due to insufficient understanding of pathogenic mechanisms driving disease progression. The etiology of NAFLD is multifactorial. The induction of both systemic and tissue inflammation consequential of skewed immune cell metabolic state, polarization, tissue recruitment, and activation are central to NAFLD progression. Here, we review the current understanding of the above stated cellular and molecular processes that govern macrophage contribution to NAFLD pathogenesis and how adipose tissue and liver crosstalk modulates macrophage function. Notably, the manipulation of such events may lead to the development of new therapies for NAFLD.

Keywords: NAFLD; cytokines; inflammation; macrophage; metabolism.

Figure 1

Macrophage subsets in health and disease. Circulating monocytes originating from the bone marrow are recruited to specific tissues and differentiate into tissue resident macrophages. In the context of systemic inflammation, circulating monocytes as well as tissue resident macrophages are activated by sensing of proinflammatory mediators (i.e., IL-6, TNF, IL-1β), chemokines and ROS or anti-inflammatory mediators (i.e., IL-10) leading to “classically” or “alternatively” activated tissue macrophages, respectively which then contribute to tissue pathology.

Figure 2

Metabolic processes within inflammatory macrophages. Macrophages are highly metabolically active cells. Their metabolic identity is impacted by inflammatory mediators. In contrast, specific metabolic pathways (Fatty acid synthesis [FAS], Glycolysis, Amino acid [AA] metabolism) regulate the type of mediators produced by these cells. During a proinflammatory state, inflammatory mediators (e.g., sugars, lipoproteins, saturated fatty acids [SFAs], cytokines [IL6, TNF]) trigger “classical” activation of circulating and tissue resident macrophages (e.g., Kupfer cells and adipose tissue macrophages [ATMs]). Circulating sugars are taken up and processed via glycolysis/TCA cycle. In addition, several intermediate metabolites, as well as amino acids L-arginine, L-tryptophan and glutamine, can impact macrophage effector functions. Sensing/uptake of excessive lipoproteins and SFAs activates the mitochondrial fatty acid oxidation (FAO) and peroxisomal fatty acid beta-oxidation (PBO) pathways to breakdown long chain and very long chain fatty acids, respectively. Excessive activation of these pathways triggers ER stress and signaling via JNK and NF-kB, resulting in amplified production of proinflammatory mediators. “Classical” macrophage activation shifts the cells toward preferential utilization of glycolytic pathways with altered enzyme activity within the tricarboxylic acid cycle (TCA) cycle generating more lactate and fast energy production in the form of ATP to generate inflammatory mediators (e.g., IL-6, TNF, IL1). Metabolism of tryptophan (L-TRP) and arginine (L-ARG) by macrophages regulates key immunologic processes. Cumulatively, these inflammatory mechanisms fuel the overall systemic and tissue inflammation, hepatocyte death, and fibrosis in turn amplifying NAFLD pathogenesis.

Figure 3

Crosstalk between tissue-specific inflammation and macrophage function in NAFLD. Schematic overview of the crosstalk between various organs, their specific immune cells and inflammatory mediators during NAFLD. Obesity-associated low-grade, chronic inflammation and altered gut microbiome impacts immune cell crosstalk between the gut, circulating monocytes/macrophages, and the liver. In addition, obesity-associated adipocyte expansion promotes hypoxia leading to adipose tissue (AT) inflammation, activation of adipose tissue macropahes (ATMs) and fuels infiltration of various immune cells and inflammatory mediator production (e.g., FFAs, ROS, cytokines, chemokines) to be sensed by circulating macrophages and hepatocytes. Collectively these processes alter hepatocellular lipid metabolism, contributing to steatosis and proinflammatory cytokine (IL-17, TNF, IFNγ, IL-6) and chemokine production (CCL2, CXCL9, CXCL10). Moreover, this inflammatory state activates hepatic stellate cells (HSCs) and Kupffer cells (KCs) in turn contributing to extracellular matrix deposition (collagen fibers) and progression to fibrosis.