title: P2X7 receptor is required for neutrophil accumulation in a mouse model of irritant contact dermatitis.
abstract: Irritant contact dermatitis (ICD) is an inflammatory reaction caused by chemical toxicity on the skin. The P2X7 receptor (P2X7R) is a key mediator of cytokine release, which recruits immune cells to sites of inflammation. We investigated the role of P2X7R in croton oil (CrO)-induced ICD using in vitro and in vivo approaches. ICD was induced in vivo by CrO application on the mouse ear and in vitro by incubation of murine macrophages and dendritic cells (DCs) with CrO and ATP. Infiltrating cells were identified by flow cytometry, histology and myeloperoxidase (MPO) determination. Effects of the ATP scavenger apyrase were assessed to investigate further the role of P2X7R in ICD. Animals were also treated with N-1330, a caspase-1 inhibitor, or with clodronate, which induces macrophage apoptosis. CrO application induced severe inflammatory Gr1(+) cell infiltration and increased MPO levels in the mouse ear. Selective P2X7R antagonism with A438079 or genetic P2X7R deletion reduced the neutrophil infiltration. Clodronate administration significantly reduced Gr1(+) cell infiltration and local IL-1β levels. In vitro experiments confirmed that A438079 or apyrase treatment prevented the increase in IL-1β that was evoked by macrophage and DC incubation with CrO and ATP. These data support a key role for P2X7 in ICD-mediated inflammation via modulation of inflammatory cells. It is tempting to suggest that P2X7R inhibition might be an alternative ICD treatment.
authors.affiliation: Programa de Pós-Graduação em Biologia Celular e Molecular, Pontificia Universidade Católica do Rio Grande do Sul-PUCRS, Porto Alegre, RS, Brazil.
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: da Silva
authors.forename: Nathalia D M
authors.initials: ND
authors.lastname: Sperotto
authors.forename: Thiago J
authors.initials: TJ
authors.lastname: Borges
authors.forename: Cristina
authors.initials: C
authors.lastname: Bonorino
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Takyia
authors.forename: Robson
authors.initials: R
authors.lastname: Coutinho-Silva
authors.forename: Maria M
authors.initials: MM
authors.lastname: Campos
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Zanin
authors.forename: Fernanda B
authors.initials: FB
authors.lastname: Morrone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D003436:Croton Oil / Q000009:adverse effects; D003877:Dermatitis, Contact / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D053583:Interleukin-1beta; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D004002:Clodronic Acid; D003436:Croton Oil