Innate Immunity and Inflammation in NAFLD/NASH

Abstract

Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.

Keywords: Cell death; Inflammation; Innate immunity; Liver disease; NASH; Therapy.

Figure 1. Immune and inflammatory responses in NAFLD/NASH

Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Fat overload of hepatocytes induces lipotoxicity and release of damage-associated molecular patterns (DAMPs) that activate both Kupffer cell (KC) and hepatic stellate cells (HSC) promoting inflammation and fibrosis respectively. Activated KCs in turn produce inflammatory cytokines and chemokines such as tumor necrosis factor-alpha (TNFα), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and C-C motif ligand 2 and 5 (CCL2 and CCL5) that contribute to injury and inflammatory necrosis in hepatocytes. KC secretion of tumor growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) also promotes fibrosis development through the mitogenic stimuli of these factors on HSC. KC population can be replenished by bone marrow-derived monocytes that amplify KC activation and recruitment through the production of Monocyte chemoattractant protein-1 MCP-1/CCL2. Bacterial-derived products also activate KCs through PAMPs (pathogen-associated molecular patterns), which originate in the intestine and reach the liver via portal circulation due to altered intestinal barrier (“leaky gut”). The role of other immune cells types in NAFLD/NASH is less clear. Natural killer (NK) cells function has been found impaired in experimental NASH and these cells could negatively regulate fibrosis through interactions with HSC. Natural killer T (NKT) cells seem to be depleted during steatosis development but increase later in the course of the disease likely contributing to inflammation and fibrosis in NASH through production of interleukin-4 (IL-4), osteopontin (OPN) and interferon-gamma (IFN-γ). Neutrophils (NEU) exacerbate the ongoing inflammatory state by contributing to macrophage recruitment and cell damage through release of myeloperoxidase, reactive oxygen species (ROS) and elastase. Dendritic cells (DC) DCs also rapidly infiltrate the liver in NASH exhibiting an activated immune phenotype but its depletion exacerbates liver inflammation suggesting that DC attenuates the inflammatory response likely through modulating KC activation. B- and T-cell responses also contribute to the feed-forward inflammatory loop through secretion of pro-inflammatory cytokines that stimulates pro-inflammatory KC activation. Finally, dysfunctional adipose tissue disturb the secretion of various adipokines including adiponectin, interleukin-6 (IL-6), leptin, TNF-α and resistin that contribute to inflammation in the liver. Also, since adiponectin is a potent anti-inflammatory and insulin sensitizing adipokine its reduced levels in NAFLD/NASH can also promote hepatic inflammatory responses.