Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

Abstract

Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.

Keywords: Kupffer Cells; inflammation; liver cancer; macrophages; steatosis.

Figure 1

Steatotic Liver Damage Establishes a Tumor Microenvironment. The primary functions of the liver are metabolism and detoxication. Nutrients from the gut are metabolized in the liver involving the insulin regulated PI3K/PTEN pathway. Wnt/β-catenin signaling also plays important role in regulating the metabolic and detoxicating functions of the liver as it regulates liver structure and zonation. Following a diet containing high fat, sugar, cholesterol, or alcohol, activation of these signals results steatosis. The consequence cell death due to steatosis and loss of liver structure leads to inflammatory cell infiltration. Inflammatory mediators produced due to liver inflammation propagate any genotoxic events as the induce the proliferation of tumor initiating cells that carry mutations of TERT, CTNNB1, TP53 and to a lesser extend PTEN and MYC as well as others. The Wnt/β-catenin, PI3K/PTEN and MAPK signaling pathways as well as cytokine and chemokine are all implicated in the proliferation of the tumor cells and play roles in propagating the initial mutagenic events.

Figure 2

Innate immune system regulate liver repair and tumorigenesis due to steatosis. The liver developed a unique immune response system that tolerate gut bacterial-induced inflammation while eliminating them at the same time. During hepatocyte homeostasis (grey cells), Kupffer cells (KC) binds to and eliminate gut bacterial while producing anti-inflammatory cytokines to inhibit CD8+ cytotoxic T cells and induce their apoptosis. At the same time, Kupffer cells also induce antigen specific CD4+ Treg cells to assume tissue repair functions. In response to chronic injury presented in NAFLD and liver steatosis (grey cells with lipid droplets), Interleukine-17 (IL-17) and interferon g (IFNγ) produce from Tregs recruit monocyte derived macrophages as well as activating a M1 proinflammatory program in Kupffer cells. The proinflammatory cytokines produced by these M1 macrophages/Kupffer cells including IL-1, IL-6, TNFα, etc induces hepatocyte proliferation to repair the damaged tissues and replace apoptotic hepatocytes due to steatosis. These proinflammatory cytokines also establishes a pro-tumor microenvironment as they propagate any genotoxic events that are present in the tumor initiating cells (orange cells). The M1 macrophage/Kupffer cells also produces chemokines to promote hepatocyte and tumor cell proliferation, leading to tissue repair and/or tumorigenesis.

Figure 3

Macrophage Reprogramming in Steatosis Driven HCC. During liver inflammation, Kupffer cells and macrophages express scavenger receptors (SR) and pattern recognition receptors (PRR) to respond to pathogens and liver damages. Activation of PRR receptors by pathogen activated molecular pattern (PAMP) and damage activated molecular pattern (DAMP) molecules reprograms hepatic macrophages to produce inflammatory cytokines/chemokines. The binding of PRRs and SRs to steatotic induced PAMP and DAMPs reprograms hepatocyte macrophages. The reprogramed M1 macrophages produce a proinflammatory cytokines where the reprogrammed M2 macrophages produce anti-inflammatory cytokines to mediate the progression of steatosis to cancer. Toll like receptor (TLRs) and NOD-like receptors (NLRs) are two common PRRs used by PAMP and DAMP to induce macrophage reprogramming. Cluster of differentiation 36 (CD36) belongs to SR family of receptors and binds to oxidized LDL. Other PRR receptors include the C-type lectin receptors (CLRs) is also expressed on the reprogrammed macrophages. Binding of these receptors to their ligands such as lipopolysaccharide (LPS), high mobility group box 1 (HMGB1) and oxidized low density lipoprotein (oxLDL) activates the innate immune response and produce cytokines and chemokines that play important roles in tumorigenesis. It also activates nuclear factor kappa B (NF-κB) and proliferator-activated receptor (PPAR) and other liver nuclear receptors such as liver X receptor (LXR) regulates transcriptional reprograming of these macrophages.

Figure 4

Programing of Hepatic Macrophages by PAMP and DAMP via PRR and SR. In normal, Kupffer cells recognize pathogen induced molecular patterns (PAMP) such as LPS coming through the portal vein. Kupffer cells clears these bacterial toxins without inducing inflammation to maintain hepatocyte homeostasis. During steatosis and steatotic injury, PRRs also bind to damage induced molecular patterns (DAMP) released by hepatocytes. The chronic injury induces proinflammatory responses from Kupffer cells as well as infiltrating macrophages. In addition, particles released by steatotic hepatocytes are also taken up by macrophages via scavenger receptors (SR). The binding of DAMP and lipid particles to PRR and SR induces the release of proinflammatory cytokines and chemokines including TNFα, IL-1, IL-6, CCL2 and 3 as well as CXCL1,2,5, and 8. These inflammatory mediators signals tissue repair and also promotes genotoxic events in liver cancer.