The Interleukin-15 and Interleukin-8 Axis as a Novel Mechanism for Recurrent Chronic Rhinosinusitis with Nasal Polyps

The prevention of postoperative recurrence after endoscopic sinus surgery (ESS) relies on targeting specific pathological mechanisms according to individuals' immunological profiles. However, essential biomarkers and biological characteristics of difficult-to-treat chronic rhinosinusitis (CRS) patients are not well-defined. The aim of this study was to explore the immunologic profiles of subgroups of CRS patients and determine the specific cytokines responsible for recalcitrant or recurrent CRS with nasal polyposis (rCRSwNP). We used 30 cytokine antibody arrays to determine the key cytokines related to recurrent polypogenesis. Enzyme-linked immunosorbent assay (ELISA) experiments were conducted to assess the levels of these key cytokines in 78 patients. Polymorphonuclear leukocytes (PMNs) isolated from nasal polyps were challenged with specific cytokines to examine the levels of enhanced interleukin (IL)-8 production. Finally, we used immunohistochemistry (IHC) staining to check for the presence and distribution of the biomarkers within nasal polyps. A cytokine antibody array revealed that IL-8, IL-13, IL-15, and IL-20 were significantly higher in the recalcitrant CRSwNP group. Subsequent ELISA screening showed a stepwise increase in tissue IL-8 levels in the CHR, CRSsNP, and CRSwNP groups. PMNs isolated from nine CRSwNP cases all demonstrated enhanced IL-8 production after IL-15 treatment. IHC staining was labeled concurrent IL-8 and IL-15 expression in areas of prominent neutrophil infiltration. Our results suggest that IL-15 within the sinonasal mucosa plays a crucial role in promoting IL-8 secretion by infiltrating PMNs in recalcitrant nasal polyps. In addition, we propose a novel therapeutic strategy targeting the anti-IL-15/IL-8 axis to treat CRS with nasal polyposis.