title: Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure.
abstract: Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9(-/-) mice).
  
  
  CONCLUSIONS
  Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.
authors.affiliation: Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Marques
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Amaral
authors.forename: Daniele A
authors.initials: DA
authors.lastname: Pires
authors.forename: Laura L
authors.initials: LL
authors.lastname: Nogueira
authors.forename: Frederico M
authors.initials: FM
authors.lastname: Soriani
authors.forename: Braulio H F
authors.initials: BH
authors.lastname: Lima
authors.forename: Gabriel A O
authors.initials: GA
authors.lastname: Lopes
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.forename: Thiago V
authors.initials: TV
authors.lastname: Avila
authors.forename: Juliana G
authors.initials: JG
authors.lastname: Melgaço
authors.forename: André G
authors.initials: AG
authors.lastname: Oliveira
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Pinto
authors.forename: Cristiano X
authors.initials: CX
authors.lastname: Lima
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: De Paula
authors.forename: Denise C
authors.initials: DC
authors.lastname: Cara
authors.forename: Maria F
authors.initials: MF
authors.lastname: Leite
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Gustavo Batista
authors.initials: GB
authors.lastname: Menezes
mesh_terms: D000082:Acetaminophen; D055371:Acute Lung Injury / Q000097:blood / Q000276:immunology; D000210:Acute-Phase Reaction / Q000276:immunology / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D002648:Child; D018920:Coculture Techniques; D004272:DNA, Mitochondrial / Q000097:blood*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000276:immunology / Q000378:metabolism; D009336:Necrosis / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D044042:Receptors, Formyl Peptide / Q000276:immunology / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D018925:Chemokines; D004272:DNA, Mitochondrial; C469988:Fpr1 protein, mouse; D016209:Interleukin-8; D024101:Mitochondrial Proteins; D044042:Receptors, Formyl Peptide; D023063:Receptors, Interleukin-8B; D051217:Toll-Like Receptor 9; D000082:Acetaminophen