Kavianpour Ava A, Ghasempour Sina, Meyer Kirsten J, Le Trieu, Cai Ruiqi, Marques Pedro Elias, Nodwell Justin R, Freeman Spencer A
Program in Cell and Systems Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Curr Biol. 2025 Sep 8;35(17):4276-4284.e5. doi: 10.1016/j.cub.2025.07.043. Epub 2025 Aug 11.
The efficient recognition and removal of apoptotic cells and extracellular vesicles (EVs) by phagocytes is critical to prevent secondary necrosis and maintain tissue homeostasis. Such detection involves receptors and bridging molecules that recognize aminophospholipids-normally restricted to the inner leaflet of healthy cells-which become exposed on the surface of dead cells and the vesicles they produce. A majority of studies focus on phosphatidylserine (PS), for which there are well-established receptors that either bind to the lipid directly or indirectly via intermediary proteins. Phosphatidylethanolamine (PE) is even more prevalent than PS in the inner leaflet of mammalian cells and also becomes exposed by the action of scramblases during cell death, though little is known about the effects of PE once scrambled. Here, we report that PE can itself serve as a phagocytic ligand for macrophages by engaging CD300 family receptors. CD300a and CD300b specifically modulated the binding and uptake of PE particles, and this process involved immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors and spleen tyrosine kinase (Syk). For bacteria, which contain PE but largely lack PS in their membranes, we report that PE engagement enabled the binding and uptake of spheroplasts and bacterial extracellular vesicles (BEVs) that were unsheathed by the cell wall. The inflammatory responses of macrophages to PE particles containing lipopolysaccharide (LPS) were also curtailed by CD300a expression. Based on these observations, we posit that the direct recognition of PE facilitates mechanisms of clearance that stand to have a broad impact on the immune response.
吞噬细胞有效识别和清除凋亡细胞及细胞外囊泡（EVs）对于预防继发性坏死和维持组织稳态至关重要。这种检测涉及识别氨基磷脂的受体和桥接分子，氨基磷脂通常局限于健康细胞的内膜，在死亡细胞及其产生的囊泡表面会暴露出来。大多数研究集中在磷脂酰丝氨酸（PS）上，针对PS有成熟的受体，这些受体可直接或通过中间蛋白间接结合该脂质。磷脂酰乙醇胺（PE）在哺乳动物细胞内膜中比PS更为普遍，并且在细胞死亡过程中也会因翻转酶的作用而暴露，但对于PE翻转后的影响知之甚少。在此，我们报告PE本身可通过与CD300家族受体结合，作为巨噬细胞的吞噬配体。CD300a和CD300b特异性调节PE颗粒的结合和摄取，这一过程涉及含免疫受体酪氨酸激活基序（ITAM）的衔接蛋白和脾酪氨酸激酶（Syk）。对于细菌，其细胞膜中含有PE但基本缺乏PS，我们报告PE的结合能够使原生质球和细菌细胞外囊泡（BEVs）被细胞壁剥离后实现结合和摄取。CD300a的表达也会抑制巨噬细胞对含有脂多糖（LPS）的PE颗粒的炎症反应。基于这些观察结果，我们推测对PE的直接识别有助于清除机制，这可能对免疫反应产生广泛影响。
