Macrophages and the development and progression of non-alcoholic fatty liver disease

Abstract

The liver is the site of first pass metabolism, detoxifying and metabolizing blood arriving from the hepatic portal vein and hepatic artery. It is made up of multiple cell types, including macrophages. These are either bona fide tissue-resident Kupffer cells (KC) of embryonic origin, or differentiated from circulating monocytes. KCs are the primary immune cells populating the liver under steady state. Liver macrophages interact with hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells to maintain homeostasis, however they are also key contributors to disease progression. Generally tolerogenic, they physiologically phagocytose foreign particles and debris from portal circulation and participate in red blood cell clearance. However as immune cells, they retain the capacity to raise an alarm to recruit other immune cells. Their aberrant function leads to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of conditions ranging from benign steatosis of the liver to steatohepatitis and cirrhosis. In NAFLD, the multiple hit hypothesis proposes that simultaneous influences from the gut and adipose tissue (AT) generate hepatic fat deposition and that inflammation plays a key role in disease progression. KCs initiate the inflammatory response as resident immune effectors, they signal to neighbouring cells and recruit monocytes that differentiated into recruited macrophages in situ. Recruited macrophages are central to amplifying the inflammatory response and causing progression of NAFLD to its fibro-inflammatory stages. Given their phagocytic capacity and their being instrumental in maintaining tissue homeostasis, KCs and recruited macrophages are fast-becoming target cell types for therapeutic intervention. We review the literature in the field on the roles of these cells in the development and progression of NAFLD, the characteristics of patients with NAFLD, animal models used in research, as well as the emerging questions. These include the gut-liver-brain axis, which when disrupted can contribute to decline in function, and a discussion on therapeutic strategies that act on the macrophage-inflammatory axis.

Keywords: Kupffer cells; fibrosis; inflammation; macrophages; non-alcoholic fatty liver disease.

Figure 1

Liver Anatomy, lobular structure, and cell types. (A) anatomic location of the liver. (B) Lobular structure of the liver. (C) Cell types in the liver: hepatocytes, Hepatic stellate cell, Kupffer cell, and Liver sinusoidal endothelial cells. Created with BioRender.com.

Figure 2

NAFLD progression and cell-to-cell signaling. (A) Development and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and advanced fibrosis. NAFLD can develop into NASH, liver cirrhosis and/or hepatocellular carcinoma (HCC) due to several factors. (B) Kupffer cells (KCs) recognize imbalances in homeostasis. Their consequent signaling allows the activation of HSCs, contributing to apoptosis and phagocytosis of damaged cells. Early infiltration and differentiation of monocytes contributes to inflammation. KC- and macrophage-derived cytokines induce HSC activation. HSCs will deposit extracellular matrix to create fibrous septa. Created with BioRender.com.

Figure 3

Classification and origins of liver macrophages. (A) Based on origin, macrophages can be classified into two subgroups. One originates from the yolk sac (Embryonic origin) and another derives from circulating monocytes that have hematopoietic origins. (B) There are two populations of liver resident Kupffer cells (KCs), including KC1s which are CD206 low and Endothelial cell-Selective Adhesion Molecule (ESAM) negative; and KC2s which are CD206high and ESAM+. KC1s express the KC markers: colony-stimulating factor-1 receptor (Csf1r), T-cell immunoglobulin and mucin domain containing 4 (Tim4), C-type lectin domain family 4 member F (Clec4F), and F4/80. In contrast, The KC2 express the markers: CD36, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1), ESAM, and CD206. Recruited macrophages can be classified based on polarity into M1 and M2. M1 macrophages are canonically inducible by lipopolysaccharide (LPS) and interferon-γ (IFN-γ), whereas interleukin (IL)-4 and IL-13 can induce M2 polarization. M1 macrophages secrete pro-inflammatory cytokines, such as IL-1β and tumor necrosis factor-α (TNF-α). Whereas, M2 macrophages primarily produce anti-inflammatory factors, such as IL-10 and transforming growth factor-β (TGF-β). In between these extremes are a number of intermediate phenotypes, and M2 macrophages can be further categorized into M2a, M2b, M2c, and M2d subtypes. Created with BioRender.com.

Figure 4

Emerging roles of the gut-liver-brain axis. (A) Barriers and signals between the gut, the liver and the brain. NT, neurotransmitters; ANS, autonomic nervous system; HPA, hypothalamic-pituitary-adrenal. (B) NAFLD and its comorbidities contribute to central nervous system (CNS) dysfunction. Created with BioRender.com.