Rôle des neutrophiles dans l'inflammation allergique associée au souffle chez le cheval, un modèle naturel d'asthme
Human asthma and equine heaves are chronic pulmonary diseases sharing several pathophysiological properties including lower airway inflammation, reversible bronchoconstriction, bronchial hyperresponsiveness, and tissue remodeling.  Clinical phenotypes of asthma are characterized in part by the inflammatory cell populations infiltrating the airways, and the presence or absence of allergy.  Heaves is a suitable animal model for the study of the poorly defined pathophysiological processes leading to airway neutrophilia.  The immune response in heaves involves Th2 cytokine expression, which is, among other features, associated to allergic inflammation (acquired immunity). Environmental dust exposure leading to clinical exacerbation of heaves contains non-specific agents derived from bacteria, molds or fungi which could also activate innate immune responses in heaves affected horses.  We studied the role of neutrophils in innate and acquired immune responses in heaves affected-horse. First, innate immune responses of neutrophils isolated from normal and heaves-affected horses to bacterial-derived products were studied.  We also assessed the effect of IL-4, a Th2 cytokine, on equine neutrophils isolated from both groups of horses. Finally, we evaluated the arginase isoforms expressed by equine neutrophils as this enzyme that takes part to the L-arginine metabolism and is thought to contribute to bronchospasm and tissue remodeling associated with asthma. Our results suggest that both neutrophils and mononuclear cells from heaves-affected horses, when compared to healthy horses, have an excessive inflammatory response to lipopolyssacharides and formylated peptides characterized by increased IL-1β, IL-8 and TNF expression. This altered innate response was associated with systemic inflammation in asymptomatic susceptible horses as high serum TNF concentrations were detected.  Furthermore, we found that equine neutrophils are activated by IL-4 and release neutrophil chemotactic factors in response to this cytokine. IL-4 also induces a distinctive activation phenotype in neutrophils that is characterized by increased expression of the pro-inflammatory cytokines (IL-8 and TNF) and receptors (IL-4Rα and CD23) potentially involved in the allergic response.   Finally, we showed that arginase 1 is not a marker of IL-4-activated equine neutrophils although they constitutively express a functionally active isoform 2 of the enzyme. The up-regulation of arginase isoforms in the peripheral lungs of horses with heaves suggests a role for arginase in this model, as it is described in the mouse, rat and guinea pig models.  Taken together, this work suggest that neutrophils could play an important role in both innate and acquired immune responses associated with heaves pathophysiology, a natural model of neutrophilic asthma.
arginase neutrophils heaves asthma innate immunity allergic response Th2-type cytokines arginase pro-inflammatory cytokines systemic inflammation cellular phenotype