The oral gingival barrier is a constantly stimulated and dynamic environment where homeostasis is often disrupted, resulting in inflammatory periodontal diseases. Type 2 diabetes (T2D) has been reported to be associated with gingival barrier dysfunction, but the effect and underlying mechanism are inconclusive. Herein, we performed single-cell RNA sequencing (scRNA-seq) of gingiva from leptin receptor-deficient mice (db/db) to examine the gingival heterogeneity in the context of T2D. Periodontal health of control mice is characterized by populations of Krt14⁺-expressing epithelial cells and Col1a1⁺-fibroblasts mediating immune homeostasis primarily through the enrichment of innate lymphoid cells. The db/db gingiva exhibited decreased epithelial/stromal ratio and dysfunctional barrier. We further observed stromal, particularly fibroblast immune hyperresponsiveness, linked to the recruitment of myeloid-derived cells at the db/db gingiva. Both scRNA-seq and histological analysis suggested the inflammatory signaling between fibroblasts and neutrophils as a potential driver of diabetes-induced periodontal damage. Notably, the “immune-like” stromal cells were wired toward the induction of gingival γδ T hyperresponsiveness in db/db mice. Our work reveals that the “immune-like” fibroblasts with transcriptional diversity are involved in the innate immune homeostasis at the diabetic gingiva. It highlights a potentially significant role of these cell types in its pathogenesis.

口腔牙龈屏障是一个不断受到刺激和动态的环境，体内平衡经常被破坏，导致炎症性牙周病。据报道，2 型糖尿病 (T2D) 与牙龈屏障功能障碍有关，但其影响和潜在机制尚无定论。在此，我们对来自瘦素受体缺陷小鼠 ( db/db )的牙龈进行了单细胞 RNA 测序 (scRNA-seq)，以检查 T2D 背景下的牙龈异质性。对照小鼠的牙周健康的特征在于表达 Krt14 ⁺的上皮细胞和 Col1a1 ⁺ - 成纤维细胞主要通过先天淋巴样细胞的富集来调节免疫稳态。分贝/分贝牙龈表现出上皮/基质比率降低和屏障功能障碍。我们进一步观察到基质，特别是成纤维细胞免疫高反应性，与db/db牙龈处的髓源细胞募集有关。scRNA-seq 和组织学分析均表明，成纤维细胞和中性粒细胞之间的炎症信号是糖尿病引起的牙周损伤的潜在驱动因素。值得注意的是，“免疫样”基质细胞与db/db小鼠牙龈 γδ T 高反应性的诱导有关。我们的工作表明，具有转录多样性的“免疫样”成纤维细胞参与了糖尿病牙龈的先天免疫稳态。它强调了这些细胞类型在其发病机制中的潜在重要作用。