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

Pieter Bogaert, Thomas Naessens, Stefaan De Koker, Benoît Hennuy, Jonathan Hacha, Muriel Smet, Didier Cataldo, Emmanuel Di Valentin, Jacques Piette, Kurt G. Tournoy, Johan Grooten

Abstract

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

  • neutrophil-predominant asthma
  • allergic inflammation
  • alveolar macrophage
  • transcriptome