FimH 黏附部分通过 Toll 样受体 4 将肿瘤微环境中的 M2 巨噬细胞极化为 M1 巨噬细胞。
adhesion portion FimH polarizes M2 macrophages to M1 macrophages in tumor microenvironment via toll-like receptor 4.
机构信息
Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
The Laboratory for Immunotherapy, Clinical Center for BioTherapy, Zhongshan Hospital, Fudan University, Shanghai, China.
出版信息
Front Immunol. 2023 Sep 1;14:1213467. doi: 10.3389/fimmu.2023.1213467. eCollection 2023.
BACKGROUND
Macrophages are key effector cells of innate immunity and play a critical role in the immune balance of disease pathogenesis, especially in the tumor microenvironment. In previous studies, we showed that FimH, an Escherichia coli adhesion portion, promoted dendritic cell activation. However, the effect of FimH in macrophage polarization has yet to be fully examined. In this study, we investigated the potential effect of FimH on macrophages, as well as the polarization from M2 to M1 macrophages, contributing to the overall antitumor effect.
METHODS
Mouse bone marrow derived macrophages and peritoneal macrophages were generated to test the effect of FimH in vitro. The expression of costimulatory molecules and production of cytokines were analyzed. The effect of FimH in the tumor-associated macrophages was examine in the B16F10-tumor bearing C57BL/6.
RESULTS
FimH was found to promote M1 macrophage activation. In addition, FimH polarized M2 macrophages, which were induced by interleukin (IL)-4 and IL-13 into M1 macrophages were dependent on toll-like receptor 4 and myeloid differentiation factor 2. Moreover, FimH reprogramed the tumor-associated macrophage (TAM) into M1 macrophages in B16 melanoma tumor-bearing mice and promoted an inflammatory reaction in the tumor microenvironment (TME). Furthermore, FimH promoted M1 macrophage activation, as well as the reversion of M2 macrophages into M1 macrophages in humans. Finally, FimH treatment was found to enhance the anti-cancer immunity of anti-PD-L1 antibody by the induction of M1 polarization from TAM.
CONCLUSION
This study demonstrated the potential effect of FimH on the activation of macrophages, responsible for the repolarization of M2 macrophages into the M1 phenotype via the TLR4 signaling pathway. Moreover, FimH could also reprogram TAM polarization to the M1 status in the TME, as well as enhance the anti-tumor activity of immune checkpoint blockade.
背景
巨噬细胞是天然免疫的关键效应细胞，在疾病发病机制的免疫平衡中发挥着关键作用，尤其是在肿瘤微环境中。在之前的研究中，我们表明大肠杆菌黏附部分 FimH 可促进树突状细胞的激活。然而，FimH 在巨噬细胞极化中的作用尚未得到充分研究。在这项研究中，我们研究了 FimH 对巨噬细胞的潜在影响，以及从 M2 向 M1 巨噬细胞的极化，这有助于整体抗肿瘤作用。
方法
体外生成小鼠骨髓来源的巨噬细胞和腹腔巨噬细胞，以测试 FimH 的作用。分析共刺激分子的表达和细胞因子的产生。在 B16F10 荷瘤 C57BL/6 小鼠中检查 FimH 在肿瘤相关巨噬细胞中的作用。
结果
发现 FimH 可促进 M1 巨噬细胞的激活。此外，FimH 将由白细胞介素 (IL)-4 和 IL-13 诱导的 M2 巨噬细胞极化成 M1 巨噬细胞，这依赖于 Toll 样受体 4 和髓样分化因子 2。此外，FimH 将肿瘤相关巨噬细胞 (TAM) 在 B16 黑素瘤荷瘤小鼠中重新编程为 M1 巨噬细胞，并促进肿瘤微环境 (TME) 中的炎症反应。此外，FimH 促进 M1 巨噬细胞的激活，并使 M2 巨噬细胞向 M1 表型逆转。最后，FimH 治疗通过诱导 TAM 从 M2 向 M1 极化，增强了抗 PD-L1 抗体的抗癌免疫。
结论
这项研究表明，FimH 对巨噬细胞的激活具有潜在作用，通过 TLR4 信号通路负责将 M2 巨噬细胞重新极化为 M1 表型。此外，FimH 还可以将 TAM 极化为 TME 中的 M1 状态，并增强免疫检查点阻断的抗肿瘤活性。
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