title: GRPR antagonist protects from drug-induced liver injury by impairing neutrophil chemotaxis and motility.
abstract: Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2.
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Instituto de Pesquisas Biomédicas (IPB), Porto Alegre, RS, Brazil.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Czepielewski
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Instituto de Pesquisas Biomédicas (IPB), Porto Alegre, RS, Brazil.
authors.forename: Natália
authors.initials: N
authors.lastname: Jaeger
authors.affiliation: Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, UFMG, Belo Horizonte, MG, Brazil.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Marques
authors.affiliation: Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Maísa M
authors.initials: MM
authors.lastname: Antunes
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Instituto de Pesquisas Biomédicas (IPB), Porto Alegre, RS, Brazil.
authors.forename: Maurício M
authors.initials: MM
authors.lastname: Rigo
authors.affiliation: Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Débora M
authors.initials: DM
authors.lastname: Alvarenga
authors.affiliation: Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Rafaela V
authors.initials: RV
authors.lastname: Pereira
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Instituto de Pesquisas Biomédicas (IPB), Porto Alegre, RS, Brazil.
authors.forename: Rodrigo D
authors.initials: RD
authors.lastname: da Silva
authors.affiliation: Laboratório de Anatomia Patológica do Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
authors.forename: Tiago G
authors.initials: TG
authors.lastname: Lopes
authors.affiliation: Laboratório de Anatomia Patológica do Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
authors.forename: Vinícius D
authors.initials: VD
authors.lastname: da Silva
authors.affiliation: Laboratório de Imunologia Clínica e Experimental, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
authors.forename: Bárbara N
authors.initials: BN
authors.lastname: Porto
authors.affiliation: Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Menezes
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Instituto de Pesquisas Biomédicas (IPB), Porto Alegre, RS, Brazil.|Department of Surgery, School of Medicine, University of California at San Diego, La Jolla, California.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bonorino
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016209:Interleukin-8; D010446:Peptide Fragments; D018004:Receptors, Bombesin; D023063:Receptors, Interleukin-8B; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D001839:Bombesin
keywords: Acetaminophen; Acute liver failure; Chemotaxis; GRPR antagonist; Neutrophil