Sekar Jinendiran, Solis Norma V, Miao Jian, Millet Nicolas, Tom Bryce, Quintanilla Derek, Pellon Aize, Moyes David L, Gogos Joseph A, Rossiter Harry B, Filler Scott G, Netea Mihai G, Yee Jennifer K, Swidergall Marc
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA, USA.
The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
bioRxiv. 2025 Jul 17:2025.07.11.664387. doi: 10.1101/2025.07.11.664387.
Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.
屏障部位的上皮细胞正逐渐成为固有免疫记忆的积极参与者，但其潜在的代谢和表观遗传机制仍不清楚。在这里，我们发现了口腔上皮细胞中一种以前未被认识的训练免疫形式，它能增强对真菌感染的保护作用。使用小鼠模型，我们表明黏膜暴露于[具体物质未给出]可赋予持续的保护性记忆，这种记忆独立于适应性免疫和髓样细胞。从机制上讲，黏膜记忆由上皮细胞中脯氨酸脱氢酶（Prodh）介导的脯氨酸分解代谢驱动，它维持线粒体功能、表观遗传重塑，并在二次刺激时促进细胞因子产生。与免疫细胞中的经典训练免疫不同，上皮记忆独立于糖酵解，但部分由肉碱棕榈酰转移酶-I（CPT1）介导的脂肪酸氧化维持。这些发现揭示了一个独特的代谢-表观遗传轴，它是口腔黏膜长期上皮记忆的基础，并揭示了黏膜抵御真菌病原体的新型非造血机制。
