University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Nat Cardiovasc Res. 2024 May;3(5):594-611. doi: 10.1038/s44161-024-00470-8. Epub 2024 May 17.
Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis.
高脂血症时造血龛的失调促进了病理性白细胞的产生，从而推动了动脉粥样硬化的发生。尽管造血主要发生在骨髓中，但在动脉粥样硬化期间，这种情况也发生在脾脏中。骨髓龛细胞，特别是内皮细胞，在动脉粥样硬化中已经得到了研究，尽管对于脾内皮细胞如何对动脉粥样硬化环境做出反应知之甚少。在这里，我们显示了在动脉粥样硬化期间，与骨髓内皮细胞相比，脾脏内皮细胞中存在独特的失调途径，包括脂质代谢和内吞作用途径的紊乱。作为这一反应的一部分，我们确定混合谱系激酶结构域样（MLKL）蛋白作为脾而非骨髓髓样生成的抑制剂。沉默脾内皮细胞中的 MLKL 会导致内体运输和脂质积累效率低下，最终促进参与斑块形成的髓样细胞的产生。这些研究确定了 MLKL 的内吞作用作为脾内皮细胞维持、脾造血以及随后动脉粥样硬化的关键机制。
