Jeff and Penny Vinik Center for Translational Immunology Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass.
Department of Otolaryngology, Head and Neck Surgery, Brigham and Women's Hospital, Boston, Mass.
J Allergy Clin Immunol. 2023 Jun;151(6):1536-1549. doi: 10.1016/j.jaci.2023.01.030. Epub 2023 Feb 17.
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown.
We sought to determine the role of T2 cytokines in regulating airway BCs.
Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration.
Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63KRT5NGFR BCs. In the sinonasal mucosa, BCAM BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP.
These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.
伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP）是一种 2 型（T2）炎症性疾病，与气道基底细胞（BC）数量增加有关。最近的研究已经确定了转录上不同的 BC，但支持或抑制人 BC 增殖和分化的分子途径在很大程度上仍是未知的。
我们旨在确定 T2 细胞因子在调节气道 BC 中的作用。
对鼻窦和肺气道上皮细胞的单细胞和批量 RNA 测序进行了分析。在存在和不存在 IL-4R 信号转导抑制剂的情况下，用 IL-4 和 IL-13 刺激人鼻窦 BC。对人鼻窦组织和鼠气道进行共聚焦分析。对鼠 BC 亚群进行 RNA 测序和功能测定。在气管损伤和再生的鼠模型中进行了命运标记。
在人和鼠呼吸道黏膜中发现了两种 BC 亚群，其特征是基底细胞黏附分子（BCAM）的表达。BCAM 表达在 P63KRT5NGFR BC 中鉴定出气道干细胞。在鼻-鼻窦黏膜中，CRSwNP 患者中 TSLP、IL33、CCL26 和经典 BC 转录因子 TP63 表达增加的 BCAM+BC。在培养的 BC 中，IL-4/IL-13 通过胰岛素受体底物依赖性信号通路增加 BCAM 和 TP63 的表达，而该信号通路在 CRSwNP 中增加。
这些发现确立了 BCAM 作为 BC 池中的气道干细胞标志物，并表明 T2 炎症中的气道上皮重塑不仅扩展到杯状细胞化生，还支持了有利于炎症持续存在的 BC 干细胞状态。
