Abstract：
The olfactory epithelium undergoes constant neurogenesis throughout life in mammals. Several factors including key signaling pathways and inflammatory microenvironment regulate the maintenance and regeneration of the olfactory epithelium. In this study, we identify TMEM59 (also known as DCF1) as a critical regulator to the epithelial maintenance and regeneration. Single-cell RNA-Seq data show downregulation of TMEM59 in multiple epithelial cell lineages with aging. Ablation of TMEM59 leads to apparent alteration at the transcriptional level, including genes associated with olfactory transduction and inflammatory/immune response. These differentially expressed genes are key components belonging to several signaling pathways, such as NF-κB, chemokine, etc. TMEM59 deletion impairs olfactory functions, attenuates proliferation, causes loss of both mature and immature olfactory sensory neurons, and promotes infiltration of inflammatory cells, macrophages, microglia cells and neutrophils into the olfactory epithelium and lamina propria. TMEM59 deletion deteriorates regeneration of the olfactory epithelium after injury, with significant reduction in the number of proliferative cells, immature and mature sensory neurons, accompanied by the increasing number of inflammatory cells and macrophages. Anti-inflammation by dexamethasone recovers neuronal generation and olfactory functions in the TMEM59-KO animals, suggesting the correlation between TMEM59 and inflammation in regulating the epithelial maintenance. Collectively, TMEM59 regulates olfactory functions, as well as neuronal generation in the olfactory epithelium via interaction with inflammation, suggesting a potential role in therapy against olfactory dysfunction associated with inflamm-aging.
摘要：
嗅觉上皮在哺乳动物的整个生命中经历持续的神经发生。包括关键信号通路和炎症微环境在内的几个因素调节嗅觉上皮的维持和再生。在这项研究中,我们确定TMEM59（也称为DCF1）是上皮维持和再生的关键调节因子。单细胞RNA-Seq数据显示TMEM59在多个上皮细胞谱系中随着衰老的下调。TMEM59的消融导致转录水平的明显改变，包括与嗅觉转导和炎症/免疫反应相关的基因。这些差异表达的基因是属于几个信号通路的关键成分。如NF-κB，趋化因子,等。TMEM59删除损害嗅觉功能，减弱增殖，导致成熟和未成熟嗅觉感觉神经元的损失，并促进炎症细胞的浸润，巨噬细胞，小胶质细胞和中性粒细胞进入嗅觉上皮和固有层。TMEM59缺失使损伤后嗅觉上皮再生恶化，随着增殖细胞数量的显著减少，不成熟和成熟的感觉神经元，伴随着炎症细胞和巨噬细胞数量的增加。地塞米松的抗炎可恢复TMEM59-KO动物的神经元生成和嗅觉功能，提示TMEM59与炎症在调节上皮维持中的相关性。总的来说，TMEM59调节嗅觉功能，以及通过与炎症相互作用在嗅觉上皮中产生神经元，提示在治疗与炎症老化相关的嗅觉功能障碍中的潜在作用。
