Activation of pyroptosis impairs basal cell differentiation in the nasal epithelium in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory sinus disease, which can be categorized into eosinophilic CRSwNP (ECRSwNP) and non-eosinophilic CRSwNP (nECRSwNP), affecting approximately 2-4 percent of the population. Recent studies have implicated pyroptosis in the pathogenesis of CRSwNP, although the underlying molecular mechanisms driving pyroptosis and its role in the onset and progression of CRSwNP remain incompletely understood. Here, we demonstrate the presence of pyroptosis features in both ECRSwNP and nECRSwNP samples, with higher signals observed in nECRSwNP compared to ECRSwNP samples. Furthermore, we identify IL-5 and IL-17A in peripheral venous serum as major triggers of pyroptosis in ECRSwNP and nECRSwNP, respectively. Additionally, activation of pyroptosis disrupts the differentiation of basal cells, favoring goblet cell differentiation, the main hallmark of CRSwNP. Intriguingly, inhibition of pyroptosis restores the balance of differentiation in basal cells by suppressing inflammation and metabolism pathways.Our findings highlight pyroptosis as a key pathological driver in CRSwNP and suggest that targeting pyroptosis may offer a novel therapeutic strategy to restore epithelial homeostasis and alleviate disease symptoms.

伴鼻息肉的慢性鼻鼻窦炎（Chronic rhinosinusitis with nasal polyps, CRSwNP）是一种慢性炎症性鼻窦疾病，可分为嗜酸性粒细胞型伴鼻息肉慢性鼻鼻窦炎（eosinophilic CRSwNP, ECRSwNP）与非嗜酸性粒细胞型伴鼻息肉慢性鼻鼻窦炎（non-eosinophilic CRSwNP, nECRSwNP）两类，人群患病率约为2%~4%。近期研究显示细胞焦亡（pyroptosis）参与了CRSwNP的发病机制，但调控细胞焦亡的潜在分子通路，以及其在CRSwNP发生与进展中的具体作用，目前尚未完全明确。本研究证实，ECRSwNP与nECRSwNP样本中均存在细胞焦亡特征，且nECRSwNP样本的细胞焦亡信号强度高于ECRSwNP样本。进一步研究发现，外周静脉血清中的白细胞介素5（IL-5）与白细胞介素17A（IL-17A）分别为ECRSwNP与nECRSwNP中细胞焦亡的主要触发因素。此外，细胞焦亡的激活会破坏基底细胞的分化平衡，偏向促进杯状细胞分化——而杯状细胞增殖正是CRSwNP的主要病理标志。值得注意的是，抑制细胞焦亡可通过抑制炎症与代谢通路，恢复基底细胞的分化稳态。本研究结果凸显了细胞焦亡作为CRSwNP关键病理驱动因子的重要性，并提示靶向细胞焦亡或可成为恢复上皮稳态、缓解疾病症状的全新治疗策略。