Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.
International Centre for Genetic Engineering and Biotechnology and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa; and.
Am J Respir Cell Mol Biol. 2024 Dec;71(6):702-717. doi: 10.1165/rcmb.2024-0208OC.
IL-4 and IL-13 play a critical role in allergic asthma pathogenesis via their common receptor IL-4Rα. However, the cell-specific role of IL-4Rα in mixed allergen (MA)-induced allergic asthma has remained unclear. Therefore, we aimed to identify the cell-specific contribution of IL-4Rα signaling in the manifestation of various pathological outcomes in mice with allergic airway disease. We compared MA-induced pathological outcomes between hematopoietic progenitor cell (HPC)- or non-HPC-specific IL-4Rα-deficient chimera, myeloid cell-specific IL-4Rα-deficient (LysMcreIL-4Rα), and airway epithelial cell-specific IL-4Rα-deficient (CCSP-Cre/IL-4Rα) mice. Chimeric mice with systemic IL-4Rα sufficiency displayed hallmark features of allergic asthma, including eosinophilic and lymphocytic infiltration, type 2 (T-helper type 2) cytokine/chemokine production, IgE production, and lung pathology. These features were markedly reduced in chimeric mice with systemic IL-4Rα deficiency. Non-HPC-specific IL-4Rα-deficient mice displayed typical inflammatory features of allergic asthma but with markedly reduced mucous cell metaplasia (MCM). Deletion of IL-4Rα signaling on airway epithelial cells, a subpopulation within the non-HPC lineage, resulted in almost complete absence of MCM. In contrast, all features of allergic asthma except for MCM and mucin production were mitigated in HPC-specific IL-4Rα-deficient chimeric mice. Deleting IL-4Rα signaling in myeloid cells, a subpopulation within the HPC lineage, significantly alleviated MA-induced allergic airway inflammatory responses, but, similar to the HPC-specific IL-4Rα-deficient chimeric mice, these mice showed significant MCM and mucin production. Our findings demonstrate that the differential allergen responsiveness seen in mice with HPC-specific and non-HPC-specific IL-4Rα deficiency is predominantly driven by the absence of IL-4Rα in myeloid cells and airway epithelial cells, respectively. Our findings also highlight distinct and mutually exclusive roles of IL-4Rα signaling in mediating pathological outcomes within the myeloid and airway epithelial cell compartments.
IL-4 和 IL-13 通过其共同受体 IL-4Rα 在过敏性哮喘发病机制中发挥关键作用。然而，IL-4Rα 在混合过敏原（MA）诱导的过敏性哮喘中的细胞特异性作用仍不清楚。因此，我们旨在确定 IL-4Rα 信号在过敏性气道疾病小鼠中各种病理结果表现中的细胞特异性贡献。我们比较了造血祖细胞（HPC）或非 HPC 特异性 IL-4Rα 缺陷嵌合体、髓样细胞特异性 IL-4Rα 缺陷（LysMcreIL-4Rα）和气道上皮细胞特异性 IL-4Rα 缺陷（CCSP-Cre/IL-4Rα）小鼠中 MA 诱导的病理结果。具有全身 IL-4Rα 充足的嵌合体小鼠表现出过敏性哮喘的标志性特征，包括嗜酸性粒细胞和淋巴细胞浸润、2 型（辅助性 T 细胞 2）细胞因子/趋化因子产生、IgE 产生和肺部病理学。这些特征在全身 IL-4Rα 缺陷的嵌合体小鼠中明显减少。非 HPC 特异性 IL-4Rα 缺陷小鼠表现出典型的过敏性哮喘炎症特征，但粘液细胞化生（MCM）明显减少。气道上皮细胞（非 HPC 谱系中的一个亚群）中 IL-4Rα 信号的缺失导致几乎完全没有 MCM。相比之下，除了 MCM 和粘蛋白产生外，HPC 特异性 IL-4Rα 缺陷嵌合体小鼠中的所有过敏性哮喘特征均得到缓解。髓样细胞（HPC 谱系中的一个亚群）中 IL-4Rα 信号的缺失显著减轻了 MA 诱导的过敏性气道炎症反应，但与 HPC 特异性 IL-4Rα 缺陷嵌合体小鼠一样，这些小鼠显示出明显的 MCM 和粘蛋白产生。我们的研究结果表明，HPC 特异性和非 HPC 特异性 IL-4Rα 缺陷小鼠中观察到的不同过敏原反应主要是由髓样细胞和气道上皮细胞中 IL-4Rα 的缺失驱动的。我们的研究结果还突出了 IL-4Rα 信号在介导髓样细胞和气道上皮细胞中病理结果方面的独特且相互排斥的作用。
