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, mitochondrial membrane permeability, 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.

Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products

“…In severe circumstances, liver transplantation is the only option that might possibly save the patient’s life. APAP-induced liver injury is emerging as a public health issue ( Yang et al, 2022a ).…”

Hepatic ZBTB22-mediated detoxification ameliorates acetaminophen-induced liver injury by inhibiting pregnane X receptor signaling

“…Treatment with excessive APAP leads to severe oxidative stress and activates the innate immune system in the liver, which induces persistent inflammatory response and hepatocyte damage. 27 Therefore, after confirming that the lack of ZBTB22 aggravates the level of oxidative stress in APAP-induced MPHs, inflammation, and apoptotic levels were subsequently detected. ZBTB22 deficiency increased the translocation of NFκB-p65 from the cytoplasm to the nucleus ( Figures 3 A and 3B), as well as up-regulated the protein expression levels of NF-κB-p65 in the nuclear ( Figure S4 A).…”

Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice

“…Several lines of accumulating evidence have suggested that leukocyte recruitment is essential for the development of APAP-induced hepatotoxicity [3,32,33]. Therefore, we evaluated the influence of sivelestat on intrahepatic leukocyte recruitment after the APAP challenge.…”