Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity

Abstract

Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair.

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

“…22 Also, after sterile cell death, neutrophils emigrate to sites of necrosis where they may participate in the healing and removal of cell debris. 23 However, uncontrolled neutrophil migration and activation is detrimental in several inflammatory diseases, such as endotoxemic shock, 24 alcoholic hepatitis, 25 gout, 10 arthritis, 11 obstructive cholestasis, 26 ischemia-reperfusion (I/R) injury, 12 and several others. 27 In spite of previous reports regarding the detrimental role of neutrophils in liver injury, data from distinct groups are controversial.…”

“…5,[28][29][30] Also, neutrophil depletion by anti-GR1 antibody injection may provide resistance to APAP toxicity independently of neutrophil circulating numbers. 23 In our study, we used three different approaches to investigate neutrophil contribution to ALF: (1) neutrophil depletion by anti-GR1 antibody; (2) chemokine and formyl peptide receptor antagonism; and (3) in vitro coculture of human neutrophils with HepG2 cells. We demonstrated that CXCR2 chemokines and formyl peptides work together to guide neutrophils to sites of liver necrosis, where they can cause additional liver injury, contributing to a systemic inflammatory response and further remote organ injury.…”

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

“…The above observations prompted us to examine the in vivo relevance of PGE2 as an iDAMP in two experimental systems: acetaminophen-induced hepatotoxicity and tumor cell growth. Peritoneal injection of acetaminophen induces massive necrosis of hepatocytes and evokes TNF-α production mediated by aDAMPs (26). Because PGE2 is produced by COX-2 in the liver (27), we hypothesized that this necrotic liver cell-derived PGE2 would function as iDAMP to counteract the activity of aDAMPs by suppressing inflammatory responses.…”

Highlight report: co-cultures of hepatocytes and macrophages for hepatotoxicity testing

“…It is well established that complex interactions between hepatocytes and nonparenchymal cells take place during induction of liver toxicity (Baeck and Tacke 2014; Hammad et al 2014;Hoehme et al 2010). Particularly, neutrophilic granulocytes and macrophages have been reported to aggravate the damage induced by hepatotoxic compounds (Adams et al 2010;Jaeschke et al 2012;Marques et al 2012Marques et al , 2015Dong et al 2007). Nevertheless, current in vitro testing for hepatotoxicity mostly relies on hepatocyte cultures without addition of immune cells (Grinberg et al 2014;Valente et al 2016;Arbo et al 2016;Deharde et al 2016;Ghallab et al 2016;Ramboer et al 2015;Godoy et al 2016;Hammad et al 2015).…”