The Dual Role of Innate Immune Response in Acetaminophen-Induced Liver Injury

Abstract

Acetyl-para-aminophenol (APAP), a commonly used antipyretic analgesic, is becoming increasingly toxic to the liver, resulting in a high rate of acute hepatic failure in Europe and the United States. Excessive APAP metabolism in the liver develops an APAP-protein adduct, which causes oxidative stress, MPTP opening, and hepatic necrosis. HMGB-1, HSP, nDNA, mtDNA, uric acid, and ATP are DMAPs released during hepatic necrosis. DMAPs attach to TLR4-expressing immune cells such KCs, macrophages, and NK cells, activating them and causing them to secrete cytokines. Immune cells and their secreted cytokines have been demonstrated to have a dual function in acetaminophen-induced liver injury (AILI), with a role in either proinflammation or pro-regeneration, resulting in contradicting findings and some research confusion. Neutrophils, KCs, MoMFs, NK/NKT cells, γδT cells, DCs, and inflammasomes have pivotal roles in AILI. In this review, we summarize the dual role of innate immune cells involved in AILI and illustrate how these cells initiate innate immune responses that lead to persistent inflammation and liver damage. We also discuss the contradictory findings in the literature and possible protocols for better understanding the molecular regulatory mechanisms of AILI.

Keywords: acetyl-para-aminophenol-induced liver injury; cytokine; innate immune response; macrophages; neutrophils.

Figure 1

The metabolism of APAP and the role of innate immune response in AILI. Following oral treatment, APAP is absorbed from the gut and transported to the liver for metabolism. A large portion (80–90%) of APAP is metabolized by SULTs and UGTs. A minor (5–10%) amount of APAP was metabolized in hepatocytes by CYP450 enzymes to the reactive metabolite NAPQI. The GSH rapidly converts NAPQI forming the APAP-GSH complex. When GSH is depleted, the growing concentration of NAPQI forms harmful APAP protein adducts, resulting in oxidative stress and increased ROS production in the mitochondria of hepatocytes. Protein adducts induce phosphorylation of JNK via ASK-1, MLK-3, and RIP1/3, then induce the MPTP opening, ultimately leading to hepatocyte necrosis and liver failure. The necrotic hepatocyte released various endogenous DAMPs, upregulating the infiltration of neutrophils, monocytes/macrophages, activated KCs, DCs, NK/NKT cells, and secreted cytokines such as TNF-α, IL-1, IL-6, IL-10, etc. DAMPs also activate inflammasomes, which participate in the innate immune response by activating caspase-1 to cleave pro-ILβ, and pro-IL-18 into IL-1β and IL-18. APAP—acetyl-para-aminophenol; AILI—APAP-induced liver injury; SULTs—sulfate transferase; UGTs—UDP glucuronosyltransferase; NAPQI—N-acetyl-p-benzoquinone imine; ROS—reactive oxygen species; MAPK—mitogen-activated protein kinase; JNK—c-Jun N-terminal kinase; MPTP—mitochondrial membrane permeability transition pore; DAMPs—damage-associated molecular patterns; KCs—Kupffer cells; DCs—Dendritic cells; NK/NKT cells—natural killer cells/NKT cells; TNF-α—tumor necrosis factor-α; IL—interleukin; INF—interferon; MCP—monocyte chemoattractant protein; MIP—macrophage inflammatory protein; IP—interferon-inducible protein; GSH—glutathione; CYP450—cytochrome P450; MLK-3—maxed-lineage kinase-3; ASK-1—apoptosis signal-regulating kinase-1; MKK—MAPK kinases; RIP1/3—receptor-interacting protein-1/3.