Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.

Keywords: NAFLD; NASH; inflammation; liver; macrophages.

Fig. 1

NAFLD progression. Benign steatosis (fat accumulation in hepatocytes) can trigger inflammation in the liver (starting point for NASH). As inflammation worsens, hepatic stellate cell activation leads to extracellular matrix deposition and fibrosis. Eventually, this process facilitates tumorigenesis and development of hepatocellular carcinoma. A tumour mass can also arise directly from NASH without need for progressive fibrosis. Fibrosis in NASH is the last reversible step of NAFLD.

Fig. 2

Cellular crosstalk during NASH. (A) In homeostatic conditions, Kupffer cells (KCs) inhibit monocyte and macrophage recruitment through interleukin 10 (IL‐10) secretion. They also promote immune tolerance from T cells by inducing regulatory T cells (T_reg) and expressing programmed death ligand 1 (PD‐L1). (B) During NASH, apoptotic hepatocytes release danger‐associated molecular patterns (DAMPs) that activate KCs. Activated KCs secrete chemokines recruiting monocytes to the liver. Monocytes differentiate into macrophages in situ and produce pro‐inflammatory cytokines which drives hepatocyte death and reinforces their pro‐inflammatory phenotype. Liver macrophages are also fuelling inflammation by promoting recruitment of other immune cells and T_H17 polarisation. Additionally, KCs and recruited Ly6C^hi monocytes can trigger hepatic stellate cells (HSCs) activation through cytokine signalling. HSCs differentiation into myofibroblasts leads to production of extracellular matrix and fibrosis. On the contrary, Ly6C^low monocytes are able to inhibit this process. EV, extracellular vesicle; ICAM1, intercellular adhesion molecule 1; MMP, metalloproteinase; Mo‐MPs, monocyte‐derived macrophages; NK, natural killer; NKT cells, natural killer T cells; PGE₂, prostaglandin E₂; TGFβ, transforming growth factor β; TNF‐α, tumour necrosis factor α; VCAM1, vascular cell adhesion molecule 1; VAP1, vascular adhesion protein 1.

Fig. 3

Transcriptional control of macrophage polarisation. Toll‐like receptor (TLR) stimulation by different ligands leads to activation of different intracellular pathways. Mitogen‐activated protein kinase kinase kinase 7 (TAK1) activation ultimately leads to phosphorylation of I‐κB and c‐Jun. Phosphorylation of I‐κB enables release of NF‐κB and its translocation to the nucleus. c‐Jun phosphorylation triggers formation of the activator protein 1 (AP‐1) complex through association with c‐Fos. NF‐κB and AP‐1 can then launch transcription of pro‐inflammatory genes and cytokines. TLR4 and TLR9 ligation additionally triggers activation of interferon regulatory factor (IRF) 3, 5 and/or 7 and subsequent type I interferon (IFN) production. Cytokine signalling also drives M1‐like polarisation, notably through activation of TAK1 and Signal Transducer and Activator of Transcription (STAT) 1. M2‐like phenotype is mainly driven by cytokine signalling leading to activation of STAT5/6 and IRF3/4. In vivo, a spectrum of intermediate phenotypes exists and it is likely still unknown signalling pathways are involved in this differentiation process. HIF‐1α, hypoxia‐inducible factor 1α; HMGB1, high‐mobility group box 1; JNK, c‐Jun N‐terminal kinase; M‐CSF, macrophage colony‐stimulating factor; MyD88, myeloid differentiation primary response 88; SFAs, saturated fatty acids.