Hypoxia-inducible factor 1a activates the NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis

Background: Chronic rhinosinusitis (CRS) is an upper airway inflammation disease associated with hypoxia-mediated inflammation. The effect of hypoxia-inducible factor 1a (HIF-1a) on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in the pathogenesis of sinonasal mucosa is unclear.Objective: We investigated the effect and mechanism of HIF-1a on NLRP3 inflammasome activation in the primary human nasal epithelial cells (hNECs).Methods: We measured the expression levels of HIF-1a and the NLRP3 inflammasome in nasal biopsy samples and hNECs derived from negative controls (healthy) and patients with CRS with and without nasal polyps, then further analyzed the specific mechanism of HIF-1a regulation of the NLRP3 inflammasome and its effect on hNEC differentiation.Results: Increased mRNA and protein expression levels of HIF-1a and the NLRP3 inflammasome were found in all CRS biopsy samples. HIF-1a enhanced expression of phosphorylated NLRP3 (S295) in both HEK293T cells and hNECs; it also promoted recruitment of caspase-1 and apoptotic speck-like protein containing caspase recruitment domain (aka ASC) by NLRP3. HIF-1a also improved NLRP3's stability by preventing NLRP3 degradation caused by hypoxia-mediated inflammation. In addition, HIF-1a could also increase expression of Mucin5AC and decrease expression of a-tubulin by promoting activation of the NLRP3 inflammasome in hNECs. In addition, HIF-1a could also directly promote P63 expression in hNECs.Conclusion: HIF-1a could potentially induce cilia loss and enhance the proliferation of goblet cells, possibly mediated by the regulation of NLRP3 phosphorylation in CRS inflammation. (J Allergy Clin Immunol 2023;152:1444-59.)