BackgroundLoss of smell is a part of the diagnostic criteria for CRSwNP. Although the mechanistic understanding is poor, inhibition of IL‐4Rα and IL‐4/IL‐13 signaling improves loss of smell in CRSwNP patients. In the present study, we compare the effects of IL‐4, IL‐13, and IL‐4Rα blockade on murine olfaction and identify the underlying pathophysiological mechanisms of loss of smell.MethodsTo evaluate the effects of IL‐4 and IL‐13 on olfactory function, we administered these cytokines intranasally to BALB/c mice for 5 consecutive days and assessed their latency to find hidden food. Calcium uptake assays were conducted to measure olfactory neuronal activity in vitro and ex vivo. We also performed histological analyses, proteomics, bulk RNA sequencing, and single‐cell RNA sequencing to assess the impact of IL‐4, IL‐13, and IL‐4Rα blockade on the olfactory epithelium and to identify potential molecular or cellular correlations with smell loss in human CRSwNP patients.ResultsHere, we provide evidence for non‐redundant effects of IL‐4 and IL‐13 in olfaction, with loss of smell in mice evoked by intranasal administration of IL‐4, not IL‐13. We demonstrate that an IL‐4–IL‐4Rα axis has a direct functional impact on murine olfactory sensory neurons and evokes inflammatory cell infiltration and pathophysiologic modulation of unique molecular signatures in olfactory epithelium without compromising structural integrity. Furthermore, single‐cell analysis of olfactory epithelium reveals that IL‐4–IL‐4Rα signaling modulates neuronal crosstalk with mast cells, macrophages, and NK cells, suggesting a functional link between olfactory impairment and neuroinflammation.ConclusionCollectively, this study suggests that an IL‐4–IL‐4Rα signaling axis plays a unique pathophysiological role in olfactory dysfunction via direct effect on neurons and modulation of neuroimmune interactions.

中文翻译：

---

IL-4-IL-4Rα 轴调节嗅觉神经免疫信号传导以诱导嗅觉丧失


背景嗅觉丧失是 CRSwNP 诊断标准的一部分。虽然对机制的理解很差，但抑制 IL-4Rα 和 IL-4/IL-13 信号传导可改善 CRSwNP 患者的嗅觉丧失。在本研究中，我们比较了 IL-4、IL-13 和 IL-4Rα 阻断对小鼠嗅觉的影响，并确定了嗅觉丧失的潜在病理生理机制。方法为了评估 IL-4 和 IL-13 对嗅觉功能的影响，我们连续 5 天鼻内给予这些细胞因子 BALB/c 小鼠，并评估它们寻找隐藏食物的潜伏期。进行钙摄取测定以测量体外和离体的嗅觉神经元活动。我们还进行了组织学分析、蛋白质组学、大量 RNA 测序和单细胞 RNA 测序，以评估 IL-4、IL-13 和 IL-4Rα 阻断对嗅觉上皮的影响，并确定与人类 CRSwNP 患者嗅觉丧失的潜在分子或细胞相关性。结果在这里，我们提供了 IL-4 和 IL-13 在嗅觉中的非冗余作用的证据，鼻内施用 IL-4 而不是 IL-13 会诱发小鼠的嗅觉丧失。我们证明 IL-4-IL-4Rα 轴对小鼠嗅觉感觉神经元有直接的功能影响，并引起炎症细胞浸润和嗅觉上皮独特分子特征的病理生理调节，而不会影响结构完整性。此外，嗅觉上皮的单细胞分析显示，IL-4-IL-4Rα 信号传导调节神经元与肥大细胞、巨噬细胞和 NK 细胞的串扰，表明嗅觉障碍与神经炎症之间存在功能联系。结论总的来说，本研究表明，IL-4-IL-4Rα 信号轴通过直接影响神经元和调节神经免疫相互作用，在嗅觉功能障碍中发挥独特的病理生理作用。