Prolonged neutrophil survival at necrotic sites is a fundamental feature for tissue recovery and resolution of hepatic inflammation

Abstract

Neutrophils were classically described as powerful effectors of acute inflammation, and their main purpose was assumed to be restricted to pathogen killing through production of oxidants. As consequence, neutrophils also may lead to significant collateral damage to the healthy tissues, and after performing these tasks, these leukocytes are supposed to die within tissues. However, there is a growing body of evidence showing that neutrophils also play a pivotal role in the resolution phases of inflammation, because they can modulate tissue environment due to secretion of different kind of cytokines. Drug-induced liver injury (DILI) is a worldwide concern being one of the most prevalent causes of liver transplantation, and is well established that there is an intense neutrophil recruitment into necrotic liver during DILI. However, information if such abundant granulocyte infiltration is also linked to the tissue repairing phase of hepatic injury is still largely elusive. Here, we investigated the dynamics of neutrophil trafficking within blood, bone marrow, and liver during hepatic inflammation, and how changes in their gene expression profile could drive the resolution events during acetaminophen (APAP)-induced liver injury. We found that neutrophils remained viable during longer periods following liver damage, because they avidly patrolled necrotic areas and up-regulated pro-resolutive genes, including Tgfb, Il1r2, and Fpr2. Adoptive transference of "resolutive neutrophils" harvested from livers at 72 h after injury to mice at the initial phases of injury (6 h after APAP) significantly rescued organ injury. Thus, we provide novel insights on the role of neutrophils not only in the injury amplification, but also in the resolution phases of inflammation.

Susceptibility to Infections During Acute Liver Injury Depends on Transient Disruption of Liver Macrophage Niche

“…The tissue damage caused by APAP overdose led to an impairment in liver function measured by an increase in indocyanine green (ICG) in the serum due to a reduced depuration rate 24h after APAP administration ( Figure 1F ) . Following 72h, the serum ICG levels were reduced to similar levels found in the non-treated control group ( Figure 1F ) in line with the regenerative process of the disease ( 24 , 39 , 40 ). To get an insight into the impact of the inflammatory response in the myeloid cell compartment, we assessed the influx of neutrophils in the liver and changes in the myeloid cell populations, including liver resident Kupffer cells (KCs), monocyte subsets ( Supplementary Figure 1A ) .…”

“…Acetaminophen (APAP) is one of the most common causes of human acute liver injury and acute liver failure that can result in death ( 24 ). Here, we used a well-established mouse model of acute liver injury (ALI) ( 16 , 33 , 39 ) to investigate alterations in the myeloid cell compartment during liver damage. To induce ALI, C57BL/6 female mice were fasted for 15h and given oral gavage with 600 mg/kg of APAP diluted in warm saline ( Figure 1A ).…”

Effect of RvD1/FPR2 on inflammatory response in chorioamnionitis

“…In addition, the contribution of placental inflammation induced by FPR2 to the pathophysiology of FGR had been investigated. However, the increased expression of FPR2 was found in some diseases, such as hepatic inflammation, autoimmune encephalomyelitis, neonatal hypoxia‐ischaemic injury 36‐38 . The current study showed that the expression of FPR2 in placental tissues of CAM patients, who were carefully selected using strict clinical standards and underlying pathology, was significantly higher than PTB women without CAM.…”

Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease

“…In support of this concept, IL-1R2 was described as a critical molecule in resolving liver inflammation (66). In particular, neutrophils up-regulated IL-1R2 in a liver injury model and contributed to protecting mice from hepatic deterioration, as confirmed by the adoptive transfer of this subset in the early stage of liver damage (66).…”

“…In contrast, IL-1R2-deficiency did not affect severity and mortality following acute administration of IL-1b or LPS, suggesting that IL-1R2 is primarily involved in regulating local inflammation (65). In support of this concept, IL-1R2 was described as a critical molecule in resolving liver inflammation (66). In particular, neutrophils up-regulated IL-1R2 in a liver injury model and contributed to protecting mice from hepatic deterioration, as confirmed by the adoptive transfer of this subset in the early stage of liver damage (66).…”