Section of Dental Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Dentistry, University of Debrecen, 4012 Debrecen, Hungary.
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Cells. 2021 Mar 15;10(3):652. doi: 10.3390/cells10030652.
Heme oxygenase-1 (HO-1) plays a vital role in the catabolism of heme and yields equimolar amounts of biliverdin, carbon monoxide, and free iron. We report that macrophages engulfing either the low amount of heme-containing apoptotic thymocytes or the high amount of heme-containing eryptotic red blood cells (eRBCs) strongly upregulate HO-1. The induction by apoptotic thymocytes is dependent on soluble signals, which do not include adenylate cyclase activators but induce the p38 mitogen-activated protein (MAP) kinase pathway, while in the case of eRBCs, it is cell uptake-dependent. Both pathways might involve the regulation of BTB and CNC homology 1 (BACH1), which is the repressor transcription regulator factor of the HO-1 gene. Long-term continuous efferocytosis of apoptotic thymocytes is not affected by the loss of HO-1, but that of eRBCs is inhibited. This latter is related to an internal signaling pathway that prevents the efferocytosis-induced increase in Rac1 activity. While the uptake of apoptotic cells suppressed the basal pro-inflammatory cytokine production in wild-type macrophages, in the absence of HO-1, engulfing macrophages produced enhanced amounts of pro-inflammatory cytokines. Our data demonstrate that HO-1 is required for both the engulfment and the anti-inflammatory response parts of the efferocytosis program.
血红素加氧酶-1（HO-1）在血红素的分解代谢中起着至关重要的作用，生成等摩尔量的胆绿素、一氧化碳和游离铁。我们报告说，吞噬少量含血红素的凋亡胸腺细胞或大量含血红素的红细胞凋亡（eRBC）的巨噬细胞强烈地上调 HO-1。凋亡胸腺细胞的诱导依赖于可溶性信号，这些信号不包括腺苷酸环化酶激活剂，但诱导丝裂原活化蛋白激酶（MAPK）途径，而在 eRBC 的情况下，它依赖于细胞摄取。这两种途径可能都涉及 BTB 和 CNC 同源性 1（BACH1）的调节，BACH1 是 HO-1 基因的阻遏转录调节因子。凋亡胸腺细胞的长期连续吞噬作用不受 HO-1 缺失的影响，但 eRBC 的吞噬作用受到抑制。这与一种内部信号通路有关，该信号通路阻止吞噬作用诱导的 Rac1 活性增加。虽然凋亡细胞的摄取抑制了野生型巨噬细胞中基础促炎细胞因子的产生，但在没有 HO-1 的情况下，吞噬的巨噬细胞产生了更多的促炎细胞因子。我们的数据表明，HO-1 是吞噬作用和吞噬作用程序的抗炎反应部分所必需的。
