Tumor necrosis factor-related apoptosis-inducing ligand mediates the resolution of allergic airway inflammation induced by chronic allergen inhalation

Abstract

Allergic asthma can vanish over time either spontaneously or induced by allergen-specific immunotherapy. In mice with established airway allergic inflammation, chronic intranasal (IN) allergen challenges decreases progressively airway allergic inflammation. Here we compared the contribution of different regulatory pathways that could be associated with this phenomenon, known as local inhalational tolerance. We found that inhalational tolerance was not associated with increased number of regulatory T cells or suppressive cytokines. Instead, it was associated with increased apoptosis of airway inflammatory leukocytes revealed by annexin-V staining and the expression of apical caspase 8 and effector caspase 3. Also, the transition from acute to chronic phase was associated with a shift in the expression of pro-allergic to pro-apoptotic molecules. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was found to be a key molecule in mediating resolution of allergic inflammation because anti-TRAIL treatment blocked apoptosis and increased the infiltration of T helper type 2 (Th2) cells and eosinophils. Notably, repeated IN treatment with recombinant TRAIL in established airway allergic inflammation augmented leukocyte apoptosis and decreased the frequency of interleukin-5-producing Th2 cells and eosinophils to airways. Our data indicate that TRAIL signaling is sufficient for downmodulation of allergic airway disease, suggesting a potential therapeutic use of TRAIL for asthma treatment.

Clinical perspectives of TRAIL: insights into central nervous system disorders

“…However, there may also be a harmful relationship between levels of TRAIL and vascular inflammation and atherosclerosis, and this requires further investigation [ 29 ]. Similarly, while some authors report a potential involvement of endogenous TRAIL in the development of allergic asthma in preclinical models [ 30 ], we, among others, have shown that soluble exogenous TRAIL appears to play a protective role in the resolution phase of asthma in a model of chronic allergen inhalation [ 31 , 32 ].…”

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

“…It is now well recognized that resolution of inflammation is a key step for dampening the inflammatory response and is instrumental for regaining homeostasis . Resolution of inflammation has been considered an active and complex process associated with the induction of a proresolving programme, which includes the downregulation of leukocyte survival, production of proresolving mediators , cessation of the recruitment and effector activity of granulocytes, and clearance of apoptotic cells by efferocytosis .…”

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

“…We [3] and others [4–7] have demonstrated that long term, continuous exposure to an allergen can result in tolerance development and ultimate resolution of allergic airway disease (AAD) in a variety of murine models. Although previous investigations in long-term models of ovalbumin (OVA)-induced AAD have added tremendously to our knowledge of the tolerogenic mechanisms utilized by the mucosal immune system to suppress allergic inflammation, OVA is far less structurally and immunologically complex than the majority of human allergens [8].…”