1. Academic Validation
  2. Cellular mechanism underlying the facilitation of contractile response induced by IL-25 in mouse tracheal smooth muscle

Cellular mechanism underlying the facilitation of contractile response induced by IL-25 in mouse tracheal smooth muscle

  • Am J Physiol Lung Cell Mol Physiol. 2022 Jul 1;323(1):L27-L36. doi: 10.1152/ajplung.00468.2021.
Ze-Xin Huang 1 Zhuo-Er Qiu 1 Lei Chen 1 Xiao-Chun Hou 1 Yun-Xin Zhu 1 Wen-Liang Zhou 1 Yi-Lin Zhang 1
Affiliations

Affiliation

  • 1 School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
Abstract

Asthma is a common heterogeneous respiratory disease characterized by airway inflammation and airway hyperresponsiveness (AHR) which is associated with abnormality in smooth muscle contractility. The epithelial cell-derived cytokine IL-25 is implicated in type 2 immune pathology including asthma, whereas the underlying mechanisms have not been fully elucidated. This study aims to investigate the effects of IL-25 on mouse tracheal smooth muscle contractility and elucidate the cellular mechanisms. Incubation with IL-25 augmented the contraction of mouse tracheal smooth muscles, which could be suppressed by the L-type voltage-dependent CA2+ channel (L-VDCC) blocker nifedipine. Furthermore, IL-25 enhanced the cytosolic CA2+ signals and triggered the upregulation of α1C L-VDCC (CAV1.2) in primary cultured mouse tracheal smooth muscle cells. Knocking down IL-17RA/IL-17RB receptors or inhibiting the transforming growth factor-β-activated kinase 1 (TAK1)-tumor progression locus 2 (TPL2)-MAPK kinase 1/2 (MEK1/2)-ERK1/2-activating protein-1 (AP-1) signaling pathways suppressed the IL-25-elicited upregulation of CAV1.2 and hyperreactivity in tracheal smooth muscles. Moreover, inhibition of TPL2, ERK1/2 or L-VDCC alleviated the AHR symptom induced by IL-25 in a murine model. This study revealed that IL-25 potentiated the contraction of tracheal smooth muscle and evoked AHR via activation of TPL2-ERK1/2-CaV1.2 signaling, providing novel targets for the treatment of asthma with a high-IL-25 phenotype.

Keywords

Cav1.2; IL-25; airway hyperresponsiveness; tracheal smooth muscle.

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