title: Inflammatory signatures for eosinophilic vs. neutrophilic allergic pulmonary inflammation reveal critical regulatory checkpoints.
abstract: Contrary to the T-helper (Th)-2 bias and eosinophil-dominated bronchial inflammation encountered in most asthmatic subjects, other patients may exhibit neutrophil-predominant asthma subphenotypes, along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma subphenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic vs. neutrophilic asthma types, we developed an ovalbumin (OVA)-based mouse model of neutrophil-dominated allergic pulmonary inflammation. Consequently, we probed for particular inflammatory signatures and checkpoints underlying the immune pathology in this new model, as well as in a conventional, eosinophil-dominated asthma model. Briefly, mice were OVA sensitized using either aluminum hydroxide (alum) or complete Freund's adjuvants, followed by OVA aerosol challenge. T-cell, granulocyte, and inflammatory mediator profiles were determined, along with alveolar macrophage genomewide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/ complete Freund's adjuvants adjuvant-based sensitization, followed by allergen challenge, elicited a pulmonary inflammation that was poorly controlled by dexamethasone, and in which Th-1 and Th-17 cells additionally participated. Analysis of the overall pulmonary and alveolar macrophage inflammatory mediator profiles revealed remarkable similarities between both models. Nevertheless, we observed pronounced differences in the IL-12/IFN-γ axis and its control by IL-18 and IL-18 binding protein, but also in macrophage arachidonic acid metabolism and expression of T-cell instructive ligands. These differential signatures, superimposed onto a generic inflammatory signature, denote distinctive inflammatory checkpoints potentially involved in orchestrating neutrophil-dominated asthma.
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.forename: Thomas
authors.initials: T
authors.lastname: Naessens
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
authors.forename: Benoit
authors.initials: B
authors.lastname: Hennuy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hacha
authors.forename: Muriel
authors.initials: M
authors.lastname: Smet
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Di Valentin
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Tournoy
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D020869:Gene Expression Profiling; D018836:Inflammation Mediators / Q000032:analysis; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D008168:Lung / Q000276:immunology; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D020382:Interleukin-18; D018664:Interleukin-12; D010047:Ovalbumin; D005620:Freund's Adjuvant