State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
School of Stomatology, Nanchang University, Nanchang, China.
Int J Oral Sci. 2024 Feb 28;16(1):20. doi: 10.1038/s41368-023-00270-z.
Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss. With the progression of periodontitis, the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption. CD301b macrophages are specific to the osteoimmunology microenvironment, and are emerging as vital booster for conducting bone regeneration. However, the key upstream targets of CD301b macrophages and their potential mechanism in periodontitis remain elusive. In this study, we concentrated on the role of Tim4, a latent upstream regulator of CD301b macrophages. We first demonstrated that the transcription level of Timd4 (gene name of Tim4) in CD301b macrophages was significantly upregulated compared to CD301b macrophages via high-throughput RNA sequencing. Moreover, several Tim4-related functions such as apoptotic cell clearance, phagocytosis and engulfment were positively regulated by CD301b macrophages. The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages. The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b macrophages as periodontitis progressed. Furthermore, the deficiency of Tim4 in mice decreased CD301b macrophages and eventually magnified alveolar bone resorption in periodontitis. Additionally, Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b macrophages phenotype. In a word, Tim4 might regulate CD301b macrophages through p38 MAPK signaling pathway in periodontitis, which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.
牙周炎是一种常见的慢性炎症性疾病，可导致牙周骨破坏，并最终导致牙齿脱落。随着牙周炎的进展，牙周炎的骨免疫学微环境受损，导致病理性牙槽骨吸收的形成。CD301b 巨噬细胞是骨免疫学微环境的特异性细胞，作为促进骨再生的重要助推器而崭露头角。然而，CD301b 巨噬细胞的关键上游靶点及其在牙周炎中的潜在机制仍不清楚。在这项研究中，我们专注于 Tim4，CD301b 巨噬细胞的潜在上游调节因子的作用。我们首先通过高通量 RNA 测序证明 CD301b 巨噬细胞中的 Tim4（Tim4 的基因名称）转录水平明显高于 CD301b 巨噬细胞。此外，CD301b 巨噬细胞还正向调节几个与 Tim4 相关的功能，如凋亡细胞清除、吞噬和吞噬作用。单细胞 RNA 测序分析随后发现 Cd301b 和 Timd4 特异性共表达于巨噬细胞中。随后的流式细胞术分析表明，总巨噬细胞中 Tim4 的阳性表达率与 CD301b 巨噬细胞的比例在牙周炎进展过程中具有高度同步的动态变化。此外，小鼠中 Tim4 的缺失减少了 CD301b 巨噬细胞，最终放大了牙周炎中的牙槽骨吸收。此外，Tim4 控制 p38 MAPK 信号通路，最终介导 CD301b 巨噬细胞表型。总之，Tim4 可能通过 p38 MAPK 信号通路在牙周炎中调节 CD301b 巨噬细胞，为牙周炎的免疫调节提供了新的见解，并有助于开发牙周炎的创新治疗靶点和治疗策略。
