Inflammatory signatures for eosinophilic versus neutrophilic allergic pulmonary inflammation reveal critical regulatory checkpoints.

Contrarily to the Th-2-bias and eosinophil-dominated bronchial inflammation encountered in most asthmatics, other patients may exhibit neutrophil-predominant asthma sub-phenotypes along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma sub-phenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic versus 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 aluminium hydroxide (alum) or Complete Freund's (CFA)-adjuvants followed by OVA aerosol challenge. T-cell, granulocyte and inflammatory mediator profiles were determined along with alveolar macrophage genome-wide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/CFA-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 (BP), 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. Key words: neutrophil-predominant asthma, allergic inflammation, alveolar macrophage, transcriptome, mouse models