Böttcher Andrea, Gaipl Udo S, Fürnrohr Barbara G, Herrmann Martin, Girkontaite Irute, Kalden Joachim R, Voll Reinhard E
University of Erlangen-Nürnberg, Erlangen, Germany.
Arthritis Rheum. 2006 Mar;54(3):927-38. doi: 10.1002/art.21660.
Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well.
The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay.
Phosphatidylserine, which was exposed on necrotic as well as apoptotic cells, promoted the recognition and removal of primary necrotic lymphocytes. Several macrophage receptor systems, including the thrombospondin-CD36-alphavbeta3 complex, CD14, and the complement component C1q, contributed to the engulfment of necrotic cells. Necrotic peripheral blood lymphocytes slightly increased the lipopolysaccharide-induced secretion of interleukin-10 and reduced the secretion of tumor necrosis factor alpha in monocytes and macrophages.
Our results indicate that at least some of the receptors and adaptors mediating the uptake of apoptotic cells are also involved in the clearance of necrotic cells. Hence, necrotic cells engage phagocyte receptors such as CD36, which mediate antiinflammatory signals from apoptotic cells. Necrotic cells consequently also have the potency to provide antiinflammatory signals to phagocytes; however, these signals may be overridden by proinflammatory factors released during necrosis. These findings have implications regarding the etiopathogenesis of autoimmune diseases such as SLE, in which impaired clearance of dead cells may foster autoimmunity by the release of potential autoantigens.
未被摄取的死亡细胞可能是自身抗原的重要来源，并可能引发自身免疫性疾病，如系统性红斑狼疮（SLE）。已有多种参与凋亡细胞清除的受体被描述；然而，对于参与摄取同样会释放自身抗原的坏死细胞的受体和配体却知之甚少。
分别通过共聚焦显微镜和双色流式细胞术对人单核细胞衍生的巨噬细胞摄取自体坏死外周血淋巴细胞进行定性和定量监测。进行阻断实验以检测参与坏死细胞吞噬作用的受体和分子。通过酶联免疫吸附测定法测定脂多糖激活的单核细胞和巨噬细胞分泌的细胞因子。
暴露于坏死细胞和凋亡细胞上的磷脂酰丝氨酸促进了对原发性坏死淋巴细胞的识别和清除。包括血小板反应蛋白-CD36-αvβ3复合物、CD14和补体成分C1q在内的几种巨噬细胞受体系统参与了坏死细胞的吞噬。坏死外周血淋巴细胞略微增加了脂多糖诱导的单核细胞和巨噬细胞中白细胞介素-10的分泌，并减少了肿瘤坏死因子α的分泌。
我们的结果表明，至少一些介导凋亡细胞摄取的受体和衔接蛋白也参与坏死细胞的清除。因此，坏死细胞与吞噬细胞受体如CD36结合，后者介导来自凋亡细胞的抗炎信号。坏死细胞因此也有能力向吞噬细胞提供抗炎信号；然而，这些信号可能被坏死过程中释放的促炎因子所掩盖。这些发现对自身免疫性疾病如SLE的发病机制具有启示意义，在这类疾病中，死亡细胞清除受损可能通过潜在自身抗原的释放促进自身免疫。
