嗅觉簇细胞对基础炎症、病毒感染先天免疫反应以及静息干细胞激活、增殖和分化的调控至关重要

文献信息

中文摘要

嗅觉黏膜既是感觉器官，也是抵御细菌、病毒入侵及其他损伤的免疫屏障。目前尚不清楚不同类型的嗅觉黏膜细胞如何协调并参与这两种功能。我们旨在揭示黏膜中一类微绒毛细胞亚群——嗅觉簇细胞——在保护和重建这一重要嗅觉感觉器官中的关键作用。我们首先验证了嗅觉簇细胞中典型味觉信号蛋白及其他分子标志物的表达。对编码两种味觉信号蛋白——G蛋白亚基Gγ13和瞬时受体电位离子通道Trpm5——的Gng13和Trpm5基因进行遗传破坏，导致黏膜基础炎症升高以及静息干细胞——水平基底细胞（HBCs）——的激活增强。H1N1流感病毒鼻腔感染进一步加剧了突变黏膜的炎症并延迟了炎症消退，包括更多免疫细胞浸润、细胞因子产生和细胞死亡增加、HBC增殖及直接分化为簇细胞增加，以及嗅觉簇细胞增生延长。对培养的嗅觉上皮类器官进行细胞因子处理表明，在突变黏膜中升高的细胞因子，包括白细胞介素-4（IL-4）、IL-13和干扰素-γ（IFN-γ），能够刺激HBC激活。总之，我们的结果表明，嗅觉簇细胞在稳态条件下维持基线炎症方面发挥重要作用，并在病毒感染后改变炎症程度、调控嗅觉黏膜中HBC的激活和分化。我们的发现揭示了嗅觉簇细胞在先天免疫反应、静息干细胞激活和神经免疫相互作用中的新作用，并为预防和治疗干细胞相关嗅觉疾病（如慢性鼻窦炎和长新冠）提供了新的治疗靶点。

英文摘要

The olfactory mucosa serves as both a sensory organ and an immune barrier to protect against bacterial and viral invasion and other insults. It is unclear how different types of olfactory mucosal cells coordinate and contribute to these two functions. We set out to reveal the critical roles of a subset of microvillous cells of the mucosa, olfactory tuft cells, in protecting and reconstructing this vital olfactory sensory organ. We first validated the expression of canonical gustatory signalling proteins and other molecular markers in olfactory tuft cells. Genetic disruption of the Gng13 and Trpm5 genes that encode the two gustatory signalling proteins, G protein subunit Gγ13 and transient receptor potential ion channel Trpm5, respectively, resulted in elevated basal inflammation and enhanced activation of the quiescent stem cells-horizontal basal cells (HBCs) in the mucosa. Nasal infection of H1N1 influenza virus further exacerbated the inflammation and delayed the resolution of inflammation in the mutant mucosa, including more immune cell infiltration, augmented cytokine production and cell death, increased HBC proliferation and direct differentiation into tuft cells, and prolonged olfactory tuft cell hyperplasia. Cytokine treatment of the cultured olfactory epithelial organoids indicated that the cytokines that were found to be elevated in the mutant mucosa, including interleukin-4 (IL-4), IL-13 and interferon-γ (INF-γ), are able to stimulate HBC activation. Together, our results indicate that olfactory tuft cells play an important role in maintaining the baseline inflammation under the steady-state condition, and altering inflammatory magnitude and modulating HBC activation and differentiation in the olfactory mucosa following the viral infection. Our findings shed light on new roles of olfactory tuft cells in innate immune response, quiescent stem cell activation and neuroimmune interactions, and provide novel therapeutic targets for preventing and treating stem cell-related olfactory disorders such as chronic rhinosinusitis and long COVID.