IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways

Abstract

Background: Specific inflammatory pathways are indicated to contribute to severe asthma, but their individual involvement in the development of airway hyperresponsiveness remains unexplored.

Objective: This experimental study in human small bronchi aimed to provide insight into which of the type 2 and type 17 cytokines cause hyperresponsiveness of airway smooth muscle.

Methods: Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells were treated for 2 and 1 day(s), respectively, with 100 ng/mL of IL-4, IL-5, IL-13, or IL-17A, and contractile responses, Ca²⁺ mobilization, and receptor expression were assessed.

Results: Treatment with IL-13 increased the potency of histamine, carbachol, and leukotriene D₄ as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In human airway smooth muscle cells, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca²⁺ mobilization that was accompanied with increased mRNA expression of histamine H₁ and cysteinyl leukotriene CysLT₁ receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated upregulation of H₁ and CysLT₁ receptors, without showing an alteration of muscarinic M₃ receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca²⁺ mobilization, or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab prevented the effects of both IL-13 and IL-4 in human bronchi and human airway smooth muscle cells.

Conclusions: The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for the treatment of airway hyperresponsiveness in asthma.

Keywords: Airway smooth muscle; IL-4Rα; STAT6; airway hyperresponsiveness; bronchoconstriction explanted human tissue model; bronchoconstrictor agents; calcium signaling; dupilumab; glucocorticoid.