Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions.
Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions.
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树突状细胞成熟后原调节蛋白1表达增加，促进其成熟和免疫功能
DOI：
10.3389/fimmu.2020.587441
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yao W
中科院分区：
文献类型：
--
作者：
Liu X;Xia X;Wang X;Zhou J;Sung LA;Long J;Geng X;Zeng Z;Yao W
树突状细胞（DC）是最有效的抗原呈递细胞，DC表达共刺激性分子，并迁移到淋巴结中，以表现出抗原对T细胞的抗原知道控制直流成熟和成熟相关的功能变化的肌动蛋白结合蛋白的机制和身份。对照肌动蛋白的沉积和成核。我们发现TMOD1在骨髓来源的未成熟DC中表达，并在脂多糖（LPS）诱导的DC成熟时显着更新。与TMOD1+/+ MDC相比，TMOD1缺陷的MDC暴露了共刺激分子和趋化因子的较低表面表达受体和炎性细胞因子的分泌降低，表明TMOD1缺乏症状的DC成熟也表明TMOD1缺陷MDC也表现出受损的随机和趋化性迁移，检测到T-Cell刺激的能力，而F-肌动蛋白含量降低MDC分泌高水平的IFN-β和IL-10，并在实验性自身免疫性脑脊髓炎（EAE）小鼠中诱导免疫反应性模型，TMOD1对于通过控制TLR4信号传导和肌动蛋白细胞骨架来控制直流成熟和免疫功能至关重要。 TMOD1可能是调节直流功能的潜在目标，该策略对多种疾病的免疫疗法有益。
Dendritic cells (DCs) are the most potent antigen-presenting cells. Upon maturation, DCs express costimulatory molecules and migrate to the lymph nodes to present antigens to T cells. The actin cytoskeleton plays key roles in multiple aspects of DC functions. However, little is known about the mechanisms and identities of actin-binding proteins that control DC maturation and maturation-associated functional changes. Tropomodulin1 (Tmod1), an actin-capping protein, controls actin depolymerization and nucleation. We found that Tmod1 was expressed in bone marrow-derived immature DCs and was significantly upregulated upon lipopolysaccharide (LPS)-induced DC maturation. By characterizing LPS-induced mature DCs (mDCs) from Tmod1 knockout mice, we found that compared with Tmod1+/+ mDCs, Tmod1-deficient mDCs exhibited lower surface expression of costimulatory molecules and chemokine receptors and reduced secretion of inflammatory cytokines, suggesting that Tmod1 deficiency retarded DC maturation. Tmod1-deficient mDCs also showed impaired random and chemotactic migration, deteriorated T-cell stimulatory ability, and reduced F-actin content and cell stiffness. Furthermore, Tmod1-deficient mDCs secreted high levels of IFN-β and IL-10 and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model. Mechanistically, Tmod1 deficiency affected TLR4 signaling transduction, resulting in the decreased activity of MyD88-dependent NFκB and MAPK pathways but the increased activity of the TRIF/IRF3 pathway. Rescue with exogenous Tmod1 reversed the effect of Tmod1 deficiency on TLR4 signaling. Therefore, Tmod1 is critical in regulating DC maturation and immune functions by regulating TLR4 signaling and the actin cytoskeleton. Tmod1 may be a potential target for modulating DC functions, a strategy that would be beneficial for immunotherapy for several diseases.