Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States; Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
Biochem Biophys Res Commun. 2024 Feb 5;695:149441. doi: 10.1016/j.bbrc.2023.149441. Epub 2024 Jan 1.
Low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor protein for Wnt ligands. Yet, their role in immune cell regulation remains elusive. Here we demonstrated that genetic deletion of LRP6 in macrophages using LysM-cre Lrp6 (Lrp6) mice showed differential inhibition of inflammation in the bleomycin (BLM)-induced lung injury model and B16F10 melanoma lung metastasis model. Lrp6 mice showed normal immune cell populations in the lung and circulating blood in homeostatic conditions. In the BLM-induced lung injury model, Lrp6 mice showed a decreased number of monocyte-derived alveolar macrophages, reduced collagen deposition and alpha-smooth muscle actin (αSMA) protein levels in the lung. In B16F10 lung metastasis model, Lrp6 mice reduced lung tumor foci. Monocytic and granulocytic-derived myeloid-derived suppressor cells (M-MDSCs and G-MDSCs) were increased in the lung. In G-MDSCs, hypoxia-inducible factor 1α (HIF1α) PDL1 population was markedly decreased but not in M-MDSCs. Taken together, our results show that the role of LRP6 in macrophages is differential depending on the inflammation microenvironment in the lung.
低密度脂蛋白受体相关蛋白 6（LRP6）是 Wnt 配体的受体蛋白。然而，其在免疫细胞调节中的作用仍不清楚。在这里，我们使用 LysM-cre Lrp6（Lrp6）小鼠证明了 LRP6 在巨噬细胞中的基因缺失可在博来霉素（BLM）诱导的肺损伤模型和 B16F10 黑色素瘤肺转移模型中差异抑制炎症。Lrp6 小鼠在稳态条件下的肺和循环血液中具有正常的免疫细胞群体。在 BLM 诱导的肺损伤模型中，Lrp6 小鼠显示肺泡巨噬细胞的单核细胞衍生减少，肺胶原沉积和α-平滑肌肌动蛋白（αSMA）蛋白水平降低。在 B16F10 肺转移模型中，Lrp6 小鼠减少了肺肿瘤灶。肺中髓源性抑制细胞（M-MDSC 和 G-MDSC）的单核细胞和粒细胞衍生增加。在 G-MDSC 中，缺氧诱导因子 1α（HIF1α）PDL1 群体明显减少，但在 M-MDSC 中则没有。总之，我们的研究结果表明，LRP6 在巨噬细胞中的作用取决于肺中的炎症微环境。
