1. Prolonged neutrophil survival at necrotic sites is a fundamental feature for tissue recovery and resolution of hepatic inflammation
- Author
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Rafael M. Rezende, Gustavo B. Menezes, Maria Alice Freitas Lopes, Ariane Barros Diniz, Maísa Mota Antunes, Alan Moreira de Araujo, Camila Dutra Moreira de Miranda, Mateus Eustáquio Lopes, Brenda Naemi Nakagaki, Matheus Silvério Mattos, Kassiana Mafra, and Débora Moreira Alvarenga
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cell Survival ,Neutrophils ,medicine.medical_treatment ,Immunology ,Inflammation ,Biology ,Liver transplantation ,Granulocyte ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Receptors, Interleukin-1 Type II ,Acetaminophen ,Liver injury ,Cell Biology ,Hepatology ,medicine.disease ,Receptors, Formyl Peptide ,Up-Regulation ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Neutrophil Infiltration ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,Chemical and Drug Induced Liver Injury ,medicine.symptom ,Infiltration (medical) ,medicine.drug - 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.
- Published
- 2020