Unraveling the role of HIF-1α in allergic rhinitis: A key regulator of epithelial barrier integrity via PI3K pathway

Background: Allergic Rhinitis (AR) ranks among the most prevalent nasal disorders worldwide. Epithelial cells are the initial physiological barrier against allergen entry, and play a vital protective role. The precise role of hypoxia-inducible factor 1-alpha (HIF-1α) inhibitors in nasal epithelial cell injury in AR is still unknown, despite their confirmed association with nasal inflammation in AR models.

Methods: An interleukin-13 (IL-13)-induced AR cell model has been employed to investigate how HIF-1α inhibition impacts nasal epithelial cells (JME/CF15). Cell viability, inflammatory cytokines, mucosal remodeling factors, and the tight junction protein zonula occludens-1 (ZO-1) were evaluated using cell counting kit-8, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence. The influences of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways have been examined.

Results: PX-478 (a HIF-1α Inhibitor) alleviated IL-13-induced epithelial barrier dysfunction by upregulating ZO-1 and reducing levels of inflammatory and remodeling factors. Mechanistically, HIF-1α activated the PI3K/MEK signaling pathway, exacerbating epithelial barrier disruption and inflammatory responses. Knockdown of HIF-1α suppressed PI3K pathway activation, mitigating inflammation and restoring barrier integrity. However, these protective effects were reversed by a PI3K Agonist.

Conclusions: HIF-1α aggravates AR by promoting inflammation, mucosal remodeling, and epithelial barrier dysfunction via PI3K pathway activation. This finding not only enriches our understanding of AR pathophysiology but also highlights HIF-1α and its downstream signaling pathways as prospective therapeutic targets for AR.