AURKA Contributes to Neutrophil Activation and NETosis in Chronic Rhinosinusitis with Nasal Polyps

Abstract Introduction: Neutrophil accumulation and neutrophil extracellular trap formation (NETosis) contribute to refractory chronic rhinosinusitis with nasal polyps (CRSwNP), yet targeted therapies remain limited. Aurora kinases (AURKs), classically known as cell-cycle regulators, have recently been implicated in immune modulation. This study investigated their involvement in CRSwNP-associated neutrophilic inflammation. Methods: Public single-cell RNA sequencing data were analyzed and validated in human nasal tissues. Multiplex immunofluorescence was used to define the cellular localization of AURKA and AURKB. Primary neutrophils were used to assess the effects of Aurora kinase inhibition on inflammatory activation, NET formation, and MAPK/NF-κB signaling. Intranasal Reversine was further evaluated in an LPS-induced neutrophilic chronic rhinosinusitis model. Results: AURKA and AURKB were upregulated in CRSwNP tissues and positively associated with disease severity and inflammatory cell infiltration. AURKA showed a neutrophil-biased expression pattern and prominent localization in MPO⁺ neutrophils, whereas AURKB was more broadly distributed in epithelial cells and MBP⁺ eosinophils, with limited neutrophil expression. Reversine suppressed neutrophil activation, inflammatory cytokine expression, and NET formation, accompanied by reduced PADI4 expression and attenuated MAPK/NF-κB signaling pathway. Isoform-selective inhibition further showed that AURKA inhibition more effectively reduced neutrophil activation and NET-associated signaling than AURKB inhibition. Transcriptomic analysis confirmed that Reversine reduced pro-inflammatory and pro-NETotic signatures. In vivo, Reversine attenuated nasal mucosal inflammation, epithelial hyperplasia, neutrophil recruitment, NET formation, and inflammatory mediator expression. Conclusion: AURKA appears to be the predominant Aurora kinase associated with neutrophil activation and NETosis in CRSwNP-associated neutrophilic inflammation. Pharmacological Aurora kinase inhibition may represent a therapeutic strategy for refractory neutrophil-predominant CRSwNP.