Macrophages in Nonalcoholic Steatohepatitis: Friend Or Foe?
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Macrophages in Nonalcoholic Steatohepatitis: Friend or Foe? Authors: Joel Grunhut,1 Wei Wang,1 Berk Aykut,1 Inderdeep Gakhal,1 Alejandro Torres-Hernandez,1 *George Miller1,2 1. S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York City, New York, USA 2. Department of Cell Biology, New York University School of Medicine, New York City, New York, USA *Correspondence to [email protected] Disclosure: The authors have declared no conflicts of interest. Received: 14.11.17 Accepted: 28.02.18 Keywords: Inflammation, macrophage, steatohepatitis. Citation: EMJ Hepatol. 2018;6[1]:100-109. Abstract Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH. INTRODUCTION The progression to NASH from its less severe form of NAFLD can be predicted by the amount of inflammation present in hepatic tissue.2 Nonalcoholic steatohepatitis (NASH), a subtype Severe inflammation can contribute to the of nonalcoholic fatty liver disease (NAFLD), is progression of other liver diseases, such as one of the most prevalent ongoing liver diseases cirrhosis, fibrosis, and hepatocellular carcinoma. seen across the world. NAFLD is histologically divided into two types: nonalcoholic The cells’ first line of defence against hepatic fatty liver and NASH. There is an estimated cell injury is the activation of macrophages. 20–40% prevalence of NAFLD worldwide The increased activation of inflammatory and approximately 10–20% of those affected macrophages produces inflammatory cytokines, progress to the subtype NASH.1 NASH is which determine the progress of NASH. In this histologically characterised by the accumulation review, we aim to understand the role of the of dense lipid deposits in hepatocytes, causing resident and infiltrating macrophages present inflammation and hepatic cell injury. This injury in NASH. Additionally, we intend to summarise leads to hepatic fibrosis, the chief cause of potential mechanisms and future therapeutic hepatic and extrahepatic complications. options that aim to reduce the burden of macrophages in NASH. 100 HEPATOLOGY • May 2018 EMJ EUROPEAN MEDICAL JOURNAL KUPFFER CELLS KC clear microbes whilst keeping the hepatic area at an optimally controlled level of inflammation. This protects the rest of the Abundancy body from an excessive immune response. KC The liver has an abundance of macrophages produce and secrete anti-inflammatory signals that spur the development of NASH by means to respond to lipotoxicity, including interleukin of extensive inflammatory pathways resulting (IL)-10 in response to lipopolysaccharide 7 from activated macrophages. It is estimated (LPS). In this manner, a balanced response is that for every 100 hepatocytes, there are an produced by KC. Additionally, KC participate additional 20–40 macrophages supplementing in immunosuppression by expressing high amounts of T cell suppression molecules and the hepatocytes.3 The majority of macrophages low levels of costimulatory molecules.8 present in liver tissue are the self-renewing, resident phagocytic Kupffer cells (KC). These In conclusion, KC maintain homeostasis and govern are split into M1 and M2 subsets that, in a inflammation in the liver microenvironment. healthy liver, balance each other’s functions. Subtypes Topology There are two main subsets of inflammatory KC reside in liver sinusoids, the portal tract, macrophages that are separated based and hepatic lymph nodes at the crossroads of upon their terminal differentiation stage: capillary-level confluence of the portal vein and the proinflammatory M1 and immunoregulatory hepatic artery tributaries. At that junction they M2 macrophages. These macrophages perform are in an environment that contains various multiple functions, such as cytokine and inflammatory agents as a result of hepatic chemokine secretion, leukocyte adhesion, circulation. KC distribution within the liver acinus phagocytosis, and cellular crosstalk. Later is correlated with the acinar concentration studies9,10 have shown that the M2 type gradient of immune reactive substrates and expands to include many other macrophages other regulatory factors. with vast differences in their biochemistry and physiology, leading to a classification system Functionality based on a full spectrum. M2 macrophages have been subdivided into M2a, M2b, and M2c, The main function of KC is to detect and each with different regulators, marker proteins, destroy pathogens, cell debris, and bacterial- and special functional activity.9 M1 macrophages derived products in the hepatic circulation by are characterised by expression of high phagocytosis, preventing the general circulation levels of proinflammatory cytokines, reactive of such pathogens. In healthy livers, KC fulfill intermediates, and promotion of a T helper the dual function of clearing these pathogens cell (Th)1 response. M2 macrophages exhibit while keeping a low and balanced level phagocytic activity, tissue remodelling, and of inflammation. KC use microbe-associated tumour progression. A more recent study10 molecular pathways to bind microbes or has shown that the balance of M1 and M2 microbe ligands. KC function via pattern macrophages regulates inflammation in the recognition receptors (PRR) that can be divided liver and is the underlying factor in NASH when into two classes: toll-like receptors (TLR) and the levels of each macrophage subtype are NOD-like receptors (NLR).4 These receptors unbalanced (Figure 1). detect danger signals, including pathogen- associated molecular patterns (PAMP) and Activation of M2 Type damage-associated molecular patterns (DAMP), M2 macrophages are primarily responsible for which leads to the activation of inflammatory wound healing and exhibit anti-inflammatory pathways. KC are then responsible for properties. M2 macrophages are induced and clearing these microbes via phagocytosis activated by IL-4, IL-10, IL-13, IL-33, tumour to prevent them from penetrating general growth factor (TGF)-α, TGF-β, peroxisome circulation.5 Additionally, KC may be activated proliferator-activated receptors (PPAR)-γ, and by metabolically driven activated signals.6 possibly PPAR-δ.11-13 Creative Commons Attribution-Non Commercial 4.0 May 2018 • HEPATOLOGY 101 M1 NASH Clear microbes Use of inflammation Healthy/balanced Reduced inflammation M2 Figure 1: The balance of M1 and M2 macrophage subtypes. Kupffer cells are in balance between M1 and M2 subtypes to control inflammation. In NASH, the key marker is an imbalance of M1 causing excess inflammation. NASH: nonalcoholic steatohepatitis. IL-4 has been shown to promote the expansion receptor depletion.17 Although PPAR-δ has been of M2 macrophages by initiating Th2 shown to promote mouse M2 macrophages, differentiation and downregulating production it is still not completely known whether of proinflammatory chemotactic factors.14,15 PPAR-δ signals and functions in activation IL-4 is also an inducer of endogenous PPAR-γ of human M2 macrophages.18 Studies on ligands.13 IL-10 downregulates Th1 cytokine human M2 macrophages were performed on expression and suppresses antigen presentation. atherosclerotic lesions and may give different IL-13 induces secretion of TGF-β and results in NASH-derived hepatic cells. allows for alternative macrophage activation, M2 macrophages produce anti-inflammatory allergic inflammation, and immunoglobulin and profibrotic cytokines. In response to IL-4 and (Ig)E secretion. IL-13, M2 macrophages promote Th2 responses.9 PPAR-γ primarily controls the expression of Additionally, M2 macrophages express high levels gene networks involved in adipogenesis, lipid of arginase, which promotes anti-inflammatory metabolism, inflammation, and the maintenance responses and increases mannose receptor 19 of metabolic homeostasis. Activation of PPAR-γ expression (Figure 2). inhibits inflammatory gene expression by Activation of M1 Type preventing the inflammatory signal-specific removal of the corepressor complex.16 In addition, In NASH, KC are the first macrophages to be studies have shown that PPAR-δ regulates activated and thus are of critical importance in the an anti-inflammatory switch that proceeds progression of NAFLD.19 The classically activated through a ligand activation and genetic macrophages, the M1 type, promote inflammation. 102 HEPATOLOGY • May 2018 EMJ EUROPEAN MEDICAL JOURNAL IL-10 IL-4 IL-13 PPAR-γ PPAR-δ Inflammatory Th1 TGF-β Inflammation Inflammation factors Antigen presentation Th2 Anti-inflammatory cytokines TH2 Araginase Anti-inflammation M2 macrophage Mannose receptor Figure 2: Activation and promotion of M2 type macrophages. The activation of M2 macrophages is caused by cell signals, including IL-10, IL-4, IL-13, PPAR-γ, and perhaps PPAR-δ. These lead to the reduction of inflammatory factors, downregulation of Th1 cytokine expression, suppression of antigen presentation, and alternative macrophage activation, which ultimately leads to the production