Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Cancer Care and Biology Program, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland 4102, Australia.
J Immunol. 2019 May 15;202(10):2982-2990. doi: 10.4049/jimmunol.1701443. Epub 2019 Apr 5.
Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from and mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling.
胆红素还原酶 (BVR)-A 是一种多功能酶，可将胆红素还原为胆红素，同时也是一种信号分子，具有细胞保护和免疫调节作用。我们最近表明，胆红素还原酶可抑制 RAW 264.7 巨噬细胞中补体激活片段 5a 受体 1（C5aR1）的表达。在这项研究中，我们通过调节 C5aR1 来研究 BVR-A 在确定巨噬细胞炎症表型和功能中的作用。我们评估了 C5aR1、M1 样巨噬细胞标志物（包括趋化因子（RANTES、IP-10））的表达，以及骨髓来源的巨噬细胞对 LPS 和 C5a 的趋化反应， 和 小鼠（骨髓细胞中 BVR-A 的条件性缺失）。对 LPS 的反应中，来自 的巨噬细胞显示出 C5aR1 以及趋化因子（RANTES、IP10）的水平显著升高，但炎症标志物（如 iNOS 和 TNF）没有升高。在脂多糖血症模型中，也观察到 小鼠的腹腔巨噬细胞和几种组织中 C5aR1 表达增加。此外，BVR-A 的敲低导致巨噬细胞向 C5a 的趋化性增强。在存在 C5aR1 中和抗体的情况下，BVR-A 缺失对趋化性和 RANTES 表达的部分影响被阻断，证实了 C5a-C5aR1 信号在介导 BVR 作用中的作用。总之，BVR-A 通过调节 C5aR1 的表达，在调节巨噬细胞对 C5a 的趋化反应中发挥重要作用。此外，缺乏 BVR-A 的巨噬细胞的特征是表达 M1 极化相关趋化因子，其水平部分取决于 C5aR1 信号。
