Allergy immunotherapy restores airway epithelial barrier dysfunction through suppressing IL-25 -induced endoplasmic reticulum stress in asthma

Abstract

Constant exposure to allergen triggers destructive type 2 cell-mediated inflammation. The effect of allergen specific immunotherapy (SIT) in maintaining airway epithelial barrier function in asthma remains unknown. In the current study, we showed that SIT maintained airway epithelial homeostasis in mice exposed to dermatophagoides farinae (Der f), which induced increased expression of IL-25, endoplasmic reticulum (ER) stress and airway epithelial apoptosis. Meanwhile, SIT treatment ameliorated airway inflammatory infiltration and hyper-responsiveness in allergic mice. SIT treatment restored the airway epithelial integrity, attenuated Der f -induced airway epithelial ER stress and epithelial apoptosis. We also found that 4-PBA, an inhibitor of ER stress, suppressed airway epithelial ER stress and apoptosis in vitro. The pathological changes were partially induced by IL-25-induced ER stress, epithelial tight junction damage, and cell apoptosis in airways following allergen exposure. Furthermore, IL-25 induced ER stress in airway epithelial cells in vitro. The IL-25-induced airway epithelial apoptosis dependent on PERK activity was inhibited by 4-PBA. Taken together, we demonstrate that SIT is effective in allergic asthma and dependent on its depressive effect on the expression of IL-25, epithelial integrity damage, and epithelial ER stress.

Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein-coupled estrogen receptor: Probing a possible target for allergic inflammation

“…Recent evidence suggested that the disturbance of the epithelial barrier as a common feature in many allergic inflammatory disorders included food allergy, asthma, and atopic dermatitis 24,25 . And the latest study also found that in the causes of allergic asthma inflammation, the damage of the bronchial epithelial integrity was considered to be the starting point for the development of airway inflammation in asthma 26‐28 . The integrity of the epithelial barrier was dependent on TJs, AJs, and so on.…”

Mechanisms of Allergen Immunotherapy in Allergic Rhinitis

“…To date, no studies in humans have demonstrated a reduction of epithelium-derived pro-inflammatory cytokines following AIT. However, a recent study of SCIT in a murine Der f-sensitized model demonstrated a reduced IL-25 secretion and restoration of epithelial integrity by ameliorating said cytokine-related endoplasmic reticulum stress and EC apoptosis [ 99 ]. However, such findings remain to be replicated in human models.…”

Molecular Hydrogen Alleviates Asthma Through Inhibiting IL-33/ILC2 Axis

“…It has been shown that IL-33 activated ILC2s disrupted airway epithelial barrier through IL-13 mediated inhibition of expression of tight junction proteins [38]. Therefore, it would be possible to ameliorate asthma by improving airway epithelial integrity through inhabiting airway epithelial ER stress and apoptosis [39]. Molecular hydrogen indeed suppressed the activation of caspase 3 and 9 in asthmatic mouse airway tissue and restored the levels of E-cadherin and ZO-1.…”