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. 2015 Jan;1(1):17-27.
doi: 10.1016/j.jcmgh.2014.11.005.

Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis

Petra Hirsova  1 , Gregory J Gores  1
Affiliations

Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis

Petra Hirsova et al. Cell Mol Gastroenterol Hepatol. 2015 Jan.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming public health problem worldwide. A subset of patients develop an inflammatory disease, nonalcoholic steatohepatitis (NASH), characterized by steatosis, hepatocellular death, macrophage and neutrophil accumulation and varying stages of fibrosis. Hepatocyte cell death triggers the cellular inflammatory response and, therefore, reducing cell death may be salutary in the steatohepatitis disease process. Recently, a better understanding of hepatocyte apoptosis in NASH has been obtained and new information regarding other cell death modes, such as necroptosis and pyroptosis, has been reported. Hepatocyte lipotoxicity is often triggered by death receptors. In addition to causing apoptosis, death receptors have been shown to mediate proinflammatory signaling, suggesting that apoptosis in this context is not an immunologically silent process. Here we review recent developments in our understanding of hepatocyte cell death by death receptors and its mechanistic link to inflammation in NASH. We emphasize how proapoptotic signaling by death receptors may induce the release of proinflammatory extracellular vesicles, thereby recruiting and activating macrophages and promoting the steatohepatitis process. Potential therapeutic strategies are discussed based on this evolving information.

Keywords: apoptosis; caspase inhibitor; cell death; death receptors; exosomes; extracellular vesicles; fibrosis; inflammasome; inflammation; microvesicles; necroptosis; pyroptosis.

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Figures

Figure 1
Figure 1
Modes of cell death. Activation of apoptotic, necroptotic, or pyroptotic signaling pathways leads to cell death. Left panel: Upon binding of a death ligand, the intracellular domain of a death receptor recruits adaptor proteins such as Fas-associated protein with death domain (FADD) and pro-caspase 8 to form a signaling platform termed the death-inducing signaling complex (DISC). Caspase 8 undergoes proteolytic autoactivation, resulting in direct or indirect (via mitochondria) activation of caspases 3, 6, and 7, which execute the final step of cell death. Various stimuli, including endoplasmic reticulum stress, trigger apoptosis via the intrinsic pathway, where mitochondrial permeabilization is a central event. Release of proapoptotic factors from mitochondria into the cytosol activates caspase 3, 6, and 7 and cell death by apoptosis. Middle panel: Necroptosis is initiated by death receptors in cells where caspase 8 function is inhibited. Under these conditions, death receptor activation promotes formation of a necrosome, a signaling complex comprising FADD, receptor-interacting protein kinase 1 (RIP1), and RIP3. This complex induces cell death via mixed lineage kinase domain-like protein (MLKL), and probably other mediators. Right panel: Pyroptosis is a cell death mode resulting from activation of inflammasomes, including NLRP3 inflammasome. Upon activation, the intracellular receptor NLR family, pyrin domain containing 3 (NLRP3) recruits apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase 1. Cleavage-activated caspase 1 then induces cell death.
Figure 2
Figure 2
Apoptotic signaling pathways in lipotoxic hepatocyte. Hepatocyte treatment with the free fatty acid (FFA) palmitate causes ligand-independent clustering and activation of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), resulting in caspase-dependent cell death. Active caspase 8 cleaves Bid into its truncated form tBid, which translocates to mitochondria to promote the release of proapoptotic factors such as cytochrome c. FFA also causes endoplasmic reticulum stress, which via CAAT/enhancer binding homologous protein (CHOP) or c-Jun N-terminal kinase (JNK) up-regulates proapoptotic proteins p53 up-regulated modulator of apoptosis (PUMA) and Bim, and TRAIL-R2. Increased levels of PUMA and Bim facilitate hepatocyte cell death via the mitochondrial apoptotic pathway.
Figure 3
Figure 3
Proinflammatory feed-forward loop between lipotoxic hepatocytes and activated macrophages. The illustration depicts the circular feed-forward relationship between hepatocyte lipotoxicity and inflammation during nonalcoholic steatohepatitis (NASH). Lipotoxicity induces the release of extracellular vesicles from hepatocytes. These can be engulfed by hepatic resident and recruited macrophages, causing macrophage activation. Activated macrophages increase the expression of death receptor ligands such as Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL), and proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which can cause further hepatocyte apoptosis and exacerbation of inflammation. This vicious circle may be interrupted by several therapeutic strategies. IL-1β, interleukin-1β; ROCK1, Rho-associated, coiled-coil containing protein kinase 1.
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