Roles of chitinases and Th17/Th1 cytokines in mouse experimental asthma

(eng) Asthma is a chronic inflammatory disorder that is more and more frequent, and for which classical corticosteroid and bronchodilator treatments are often not efficient enough. Animal mouse models constitute a valuable research tool for dissecting asthma mechanisms and notably, have allowed to study T helper 2 lymphocyte and eosinophil contribution to the disease. Subsequent to these experimental researches, Th2-derived cytokines were extensively evaluated as therapeutic targets in humans with somewhat lukewarm results. In a first part, we aimed to validate other potential therapeutic targets than cytokines in the context of the classical mouse model of lung inflammation induced by ovalbumin (OVA) sensitization and challenge. Using an original autoimmunization method, we evaluated the neutralization of chitinase and chitinase-like protein (CLP) family in lung inflammation. Even if these proteins are now recognized as inflammatory mediators in asthma, we could not observe any beneficial effect of the autoimmunization on lung inflammation, and concluded from our results that chitinases and CLPs are not adequate candidates for antibody-based therapy. Recently, Th17-derived IL-17 was correlated to asthma, notably in severe forms of the disease, and associated to neutrophil increase in the lung. In a second part of this work, we could confirm the causative role of IL-17-A and -F, but not of IL-22, on neutrophilia in a mouse model of Th17-polarized lung inflammation generated by OVA inhalation in DO11.10 mice (transgenic for OVA-specific TCR). Surprisingly, we could observe that these mice are resistant to develop lung eosinophilia, even after the OVA-alum sensitization. We showed that IFNγ is responsible for inhibition of eosinophil infiltration, but not IL-17, which induces neutrophilia. A particular CD4+ cell population, specifically present in DO11.10 mice, was responsible for this neutrophilic polarization. We found that a significant proportion of the transgenic T cells express an additional endogenous receptor, suggesting dual antigenic specificities. This dual TCR population expressed markers of memory cells, secreted high levels of IL-17A after short-term restimulation in vitro and, after transfer, induced a lung neutrophilic response upon OVA inhalation. We suggested that this Th17-polarization of dual TCR cells is promoted by gut microflora. Taken together, our data indicate that the presence of dual TCR cells in DO11.10 mice biases the inflammatory lung response to OVA towards an IL-17-induced lung neutrophilia in DO11.10 mice, rather than an eosinophil infiltration, due to the inhibitory activity of IFNγ.