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.