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, Wuhan University, Wuhan, 430079, China.
Department of Stomatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China.
Inflammation. 2024 Feb;47(1):307-322. doi: 10.1007/s10753-023-01910-6. Epub 2023 Oct 2.
Leukemia inhibitory factor (LIF) has been recognized as a novel inflammatory modulator in inflammation-associated diseases. This study aimed to investigate the modulation of LIF in dental pulp inflammation. Experimental pulpitis was established in wild-type (WT) and Lif-deficient (Lif) mice. Histological and immunostaining analyses were conducted to assess the role of LIF in the progression of pulpitis. Mouse macrophage cell line (RAW264.7) was treated with LPS to simulate an inflammatory environment. Exogenous LIF was added to this system to examine its modulation in macrophage inflammatory response in vitro. Primary bone marrow-derived macrophages (BMDMs) from WT and Lif mice were isolated and stimulated with LPS to confirm the effect of Lif deletion on macrophage inflammatory response. Supernatants from LIF and LPS-treated human dental pulp cells (hDPCs) were collected and added to macrophages. Macrophage chemotaxis was assessed using transwell assays. The results showed an increased expression of LIF and LIFR with the progression of pulpitis, and LIFR was highly expressed in macrophages. Lif deficiency alleviated experimental pulpitis with the reduction of pro-inflammatory cytokines and macrophage infiltration. Exogenous LIF promoted inflammatory response of LPS-induced macrophages through a STAT3/p65-dependent pathway. Consistently, Lif deletion inhibited macrophage inflammatory response in vitro. Supernatants of LIF-treated hDPCs enhanced macrophage migration in LPS-induced inflammatory environment. Our findings demonstrated that LIF aggravates pulpitis by promoting macrophage inflammatory response through a STAT3/p65-dependent pathway. Furthermore, LIF plays a crucial role in driving the recruitment of macrophages to inflamed pulp tissue by promoting chemokine secretion in DPCs.
白血病抑制因子（LIF）已被认为是与炎症相关疾病中的新型炎症调节剂。本研究旨在探讨 LIF 在牙髓炎症中的调节作用。在野生型（WT）和 Lif 缺陷型（Lif）小鼠中建立实验性牙髓炎。通过组织学和免疫染色分析评估 LIF 在牙髓炎进展中的作用。用 LPS 处理小鼠巨噬细胞系（RAW264.7）模拟炎症环境。将外源性 LIF 加入该系统，以研究其在体外巨噬细胞炎症反应中的调节作用。从 WT 和 Lif 小鼠中分离出原代骨髓来源的巨噬细胞（BMDM），并用 LPS 刺激以确认 Lif 缺失对巨噬细胞炎症反应的影响。收集 LIF 和 LPS 处理的人牙髓细胞（hDPC）的上清液并添加到巨噬细胞中。使用 Transwell 测定法评估巨噬细胞趋化性。结果显示，随着牙髓炎的进展，LIF 和 LIFR 的表达增加，并且 LIFR 在巨噬细胞中高表达。Lif 缺失减轻了实验性牙髓炎，减少了促炎细胞因子和巨噬细胞浸润。外源性 LIF 通过 STAT3/p65 依赖性途径促进 LPS 诱导的巨噬细胞炎症反应。同样，Lif 缺失抑制了体外巨噬细胞的炎症反应。LIF 处理的 hDPCs 的上清液增强了 LPS 诱导的炎症环境中巨噬细胞的迁移。我们的研究结果表明，LIF 通过 STAT3/p65 依赖性途径促进巨噬细胞炎症反应，从而加重牙髓炎。此外，LIF 通过促进 DPCs 中趋化因子的分泌，在募集巨噬细胞到炎症牙髓组织中发挥关键作用。
