The complex roles of neutrophils in APAP‐induced liver injury

Abstract

Acetaminophen (APAP) is a kind of widely used drug for the treatment of pain and fever. It is reported that its overdose can cause serious liver failure. 1 In Europe and the United States, APAP-induced acute liver injury (ALI) has become one of the primary causes of liver failure and thus arises widespread concern and research in the world. 2 Abundant evidences have suggested that both innate and adaptive immune cells, such as macrophages, neutrophils and T cells, played critical roles in APAP-induced ALI. 3,4 It is now clear that neutrophils have important homeostatic functions in various organ systems including liver, 5,6 but what the role of neutrophils plays in APAP-induced ALI still remains elusive. 7,8 Neutrophils, a type of polymorphonuclear leukocytes, are the first-line guardians of the innate immune system. Normally, neutrophils are not activated and move slowly in peripheral blood circulation without direction. The half-life of neutrophils is only 6-7 hours. 9 Once the pathogen invades or the endogenous stimulants releases, the pattern recognition receptors can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Then, inflammatory reaction occurs and neutrophils are activated. 10,11 The activated neutrophils in peripheral circulation will tend to move towards the injury site. The migration of neutrophils involves rolling, activation and adhesion. 12,13 They then participate in the inflammatory process through phagocytosis, degranulation and extracellular traps (NETs). 14 On the one hand, neutrophils are drawn from the blood to sterility inflammatory site, which contribute to wound healing. On the other hand, their prolonged half-life, release of granule proteins such as myeloperoxidase (MPO), neutrophil serine proteases (NSPs), lipocalin 2 (LCN2), human neutrophil peptide (HNP), excessive infiltration and uncontrolled activation may lead to destruction of normal tissue structures and serious inflammations. 15 Therefore, how neutrophils play in APAP-induced ALI has aroused great controversy. In this review, we outline the neutrophil's

Confusoside, a dihydrochalcone glucoside, prevents acetaminophen-induced liver injury by modulating the Nrf2/NF-κB/caspase signaling pathway

“…For example, phloridzin, quercetin, and glucomannans had excellent anti-inflammatory effects for the treatment of inflammatory-related diseases by inhibiting NF-κB or MAPK pathway. 39,40 These findings were also observed in this study, where CF could effectively inhibit the expressions of p65 and p38 phosphorylation and significantly reduced the expressions of IL-1β, IL-6, TNF-α, NO, iNOS, and COX-2 expressions induced by APAP, supporting that CF had the anti-inflammatory response-ability.…”

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

“…Then, the necrotic hepatocyte subsequently releases various endogenous damage-associated molecular patterns (DAMPs) ( Figure 1 ), including high mobility group box protein 1 (HMGB-1) [ 21 ], heat shock proteins (HSPs), nuclear DNA fragments (nDNA fragments) [ 22 ] and mitochondrial DNA (mtDNA), uric acid [ 23 ], adenosine triphosphate (ATP) [ 24 ], and so on, thereby activating the innate immune response. Furthermore, necrotic hepatocytes also upregulated the infiltration of leucocytes [ 25 ], monocytes, activated Kupffer cells (KCs), and hepatic stellate cells (HSCs) [ 26 ]. KCs and bone marrow-derived monocytes/macrophages recognize DMAPs via Toll-like receptor (TLR) 4 and are activated, releasing proinflammatory cytokines and chemokines, resulting in a “cytokines storm”.…”

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

“…The activation and recruitment of neutrophils are modulated by DAMPs, other immune cells and inflammation mediators in AILI. DAMPs, including ATP, high-mobility group box1(HMGB1), release in mice after APAP challenge, induce neutrophils recruitment [ 67 – 69 ]. KCs activated by overdose-APAP release numerous pro-inflammatory mediators to recruit neutrophils to damage sites [ 45 , 70 ].…”

“…In contrary, some researchers suggested that neutrophils are not involved in the early phase of APAP hepatotoxicity [ 69 , 83 , 84 ]. Williams et al [ 83 ] , found that mice treated with extra dose of IL-1β and APAP have an increasement of neutrophils accumulation by 35% compared with APAP monotherapy, but have no significant difference in serum levels of ALT or liver necrosis.…”