title: IL-6 regulates neutrophil trafficking during acute inflammation via STAT3.
abstract: The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp130(Y757F/Y757F) mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130(Y757F/Y757F) mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STAT1/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130(Y757F/Y757F) mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130(Y757F/Y757F) mice failed to rescue the altered responses observed in gp130(Y757F/Y757F) mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response.
authors.affiliation: Department of Nephrology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.forename: Chantal S
authors.initials: CS
authors.lastname: Colmont
authors.forename: Meri
authors.initials: M
authors.lastname: Najdovska
authors.forename: Dianne
authors.initials: D
authors.lastname: Grail
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement / Q000276:immunology*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130