Efferocytosis deficiency exacerbates local inflammation and predicts recurrence in chronic rhinosinusitis with nasal polyps.

Abstract

The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3⁺ macrophages in healthy controls to efferocytosis-impaired macrophages in CRS: FCN1⁺ subset predominated in CRS without nasal polyps; FCN1⁺, IL-1β⁺, and CXCL12⁺ subsets in noneosinophilic CRSwNP; and FN1⁺ and SPP1⁺ subsets in eosinophilic CRSwNP. All these CRS-associated macrophages exhibited reduced proefferocytic receptors (CX3CR1, MerTK) and elevated antiphagocytic receptor SIRPA. Efferocytosis-related signals correlated with type 2-skewed markers. A 5-molecule signature (S1PR5, MerTK, MFGE8, CD300a, PPARδ) was identified as a predictive panel for CRSwNP recurrence, with a receiver operating characteristic area under the curve of 0.867. Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP.