Department of Implantology, School and Hospital of Stomatology, Tongji University, Shanghai, China.
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
J Dent Res. 2022 Apr;101(4):437-447. doi: 10.1177/00220345211044681. Epub 2021 Nov 1.
Periodontitis is a chronic inflammatory condition characterized by destruction of nonmineralized and mineralized connective tissues. This study evaluated the role of Trem1 (triggering receptors expressed on myeloid cells 1) in periodontitis by influencing polarization of M1 macrophages through the STAT3/HIF-1α signaling pathway. Trem1 was significantly upregulated in the gingival tissues of patients with periodontitis, as identified by high-throughput RNA sequencing, and positively correlated with levels of M1 macrophage-associated genes. The results of flow cytometry, Western blotting, and reverse transcription quantitative polymerase chain reaction showed that knockdown of Trem1 in RAW 264.7 cells decreased polarization of M1 macrophages and increased polarization of M2 macrophages, while overexpression of Trem1 exerted an opposite effect. Furthermore, a mouse model of Trem1 knockout periodontitis exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage-associated genes in periodontitis lesions and bone marrow-derived macrophages. Importantly, we found that Trem1 could regulate polarization of M1 macrophages through STAT3/HIF-1α signaling as evidenced by RNA sequencing. Moreover, inhibition of Trem1 and HIF-1α could suppress the expression level of proinflammatory cytokine (interleukin 1β) and upregulate the expression level of anti-inflammatory cytokine (interleukin 10) in periodontitis. Collectively, we identified that the Trem1/STAT3/HIF-1α axis could regulate polarization of M1 macrophages and is a potential candidate in the treatment of periodontitis.
牙周炎是一种慢性炎症性疾病，其特征是破坏非矿化和矿化的结缔组织。本研究通过影响 STAT3/HIF-1α 信号通路来调节 M1 巨噬细胞的极化，从而评估 Trem1（髓样细胞表达的触发受体 1）在牙周炎中的作用。高通量 RNA 测序表明，Trem1 在牙周炎患者的牙龈组织中显著上调，并与 M1 巨噬细胞相关基因的水平呈正相关。流式细胞术、Western blot 和逆转录定量聚合酶链反应的结果表明，RAW 264.7 细胞中 Trem1 的敲低降低了 M1 巨噬细胞的极化，增加了 M2 巨噬细胞的极化，而过表达 Trem1 则产生相反的效果。此外，Trem1 敲除牙周炎小鼠模型显示在牙周炎病变和骨髓来源的巨噬细胞中巨噬细胞浸润受限，并且 M1 巨噬细胞相关基因的表达水平降低。重要的是，我们发现 Trem1 可以通过 STAT3/HIF-1α 信号调节 M1 巨噬细胞的极化，这一点可以通过 RNA 测序得到证明。此外，抑制 Trem1 和 HIF-1α 可以抑制牙周炎中促炎细胞因子（白细胞介素 1β）的表达水平，并上调抗炎细胞因子（白细胞介素 10）的表达水平。总之，我们确定了 Trem1/STAT3/HIF-1α 轴可以调节 M1 巨噬细胞的极化，是治疗牙周炎的潜在候选药物。
