Interaction of Alt a 1 with SLC22A17 in the airway mucosa

Abstract

Background: Despite all the efforts made up to now, the reasons that facilitate a protein becoming an allergen have not been elucidated yet. Alt a 1 protein is the major fungal allergen responsible for chronic asthma, but little is known about its immunological activity. Our main purpose was to investigate the ligand-dependent interactions of Alt a 1 in the human airway epithelium.Methods: Alt a 1 with and without its ligand (holo-and apo-forms) was incubated with the pulmonary epithelial monolayer model, Calu-3 cells. Allergen transport and cytokine production were measured. Pull-down and immunofluorescence assays were employed to identify the receptor of Alt a 1 using the epithelial cell model and mouse tissues. Receptor-allergen-ligand interactions were analyzed by computational modeling. Results:The holo-form could activate human monocytes, PBMCs, and polarized airway epithelial (Calu-3) cell lines. The allergen was also transported through the monolayer, without any alteration of the epithelial integrity (TEER). Alt a 1 also induced the production of proinflammatory IL8 and specific epithelial cytokines (IL33 and IL25) by Calu-3 cells. The interaction between epithelial cells and holo-Alt a 1 was found to be mediated by the SLC22A17 receptor, and its recognition of Alt a 1 was explained in structural terms. Conclusions:Our findings identified the Alt a 1 ligand as a central player in the interaction of the allergen with airway mucosa, shedding light into its potential role in the immunological response, while unveiling its potential as a new target for therapy intervention.

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…Similarly, there is also evidence showing goblet cell hyperplasia, excessive mucus productions, basal cell hyperplasia, and basement membrane thickening in the upper airways of patients with CRS with nasal polyp (CRSwNP) 26‐28 . The reprogramming process in the upper airway is related to subepithelial fibrosis, basement membrane thickening, and disease severity, which is similar to what occurs in the lower airway 29,30 …”

The allergenic activity and clinical impact of individual IgE-antibody binding molecules from indoor allergen sources

“…Alt a 1 in its tetrameric form interacts with the solute carrier family 22 member 17 (SLC22A17) receptor on the airway epithelium, undergoes receptor-mediated endocytosis and without evident alterations of the epithelial integrity, induces the expression of proinflammatory cytokines such as IL-8, IL-33 and IL-25. 178 Moreover, Alt a 1 has been found to induce several cytokines and chemokines in bronchial epithelial cells, including CXCL1, CXCL2, CXCL3, IL-8 and CCL2 and this effect was dependent and mediated by pattern recognition receptors and adaptor molecules such as TLR2, TLR4, MyD88, and TIRAP. 179 Alt a 1, either in its natural or recombinant form is a reliable tool for the diagnosis of A. alternata sensitization and induces skin prick reactivity comparable with that produced by the A. alternata extract.…”

Alternaria as an Inducer of Allergic Sensitization

“…Alt a 1 is released in large quantities by spores at pH values around 5.0–6.5, carrying its flavonol and catechol ligands [ 37 ]. On the one hand, Alt a 1 interacts with the SLC22A17 receptor in bronchial epithelial cells and mediates the production of IL-33 and IL-25 [ 62 ]. On the other hand, this interaction does not result in an increase in barrier permeability, and thus does not explain how Alt a 1 reaches the basolateral side and comes in contact with the immune system cells.…”