Clostridium perfringens α-toxin up-regulates plasma membrane CD11b expression on murine neutrophils by changing intracellular localization
Clostridium perfringens α-toxin up-regulates plasma membrane CD11b expression on murine neutrophils by changing intracellular localization
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产气荚膜梭菌 α-毒素通过改变细胞内定位上调小鼠中性粒细胞质膜 CD11b 表达
DOI：
10.1016/j.bbamem.2022.184054
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Nagahama Masahiro
中科院分区：
文献类型：
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作者：
Takehara Masaya;Kobayashi Keiko;Nagahama Masahiro
产气荚膜梭菌A型感染引起的气性坏疽是一种高致死性的软组织感染，其特征是组织坏死迅速扩散。这种组织破坏与血流的深度衰减有关，伴随着血管中血小板-白细胞聚集体的形成。几项研究已确定α毒素（具有鞘磷脂酶和磷脂酶C活性）是通过激活血小板gpIIbIIIa形成聚集体的主要毒力因子。在这里，我们表明，α-毒素极大地，迅速增加质膜定位的CD 11b，通过纤维蛋白原结合到血小板gpIIbIIIa，在小鼠中性粒细胞。有趣的是，短期α毒素处理对中性粒细胞中的基因表达谱几乎没有影响，并且毒素不会改变全细胞裂解物中CD 11b的总蛋白表达水平。以下分析表明，在完整细胞中，CD 11b定位于胞内囊泡，但在α毒素处理的细胞中，定位变为胞质膜。这些结果表明，CD 11b被α-毒素募集到细胞质膜。以前，我们报道了α-毒素通过其鞘磷脂酶活性促进小鼠中性粒细胞中神经酰胺的形成。有趣的是，一种合成的细胞渗透性神经酰胺类似物C2-神经酰胺增加了CD 11b的质膜定位，表明α-毒素产生的神经酰胺将CD 11b募集到细胞质膜，以促进血小板-白细胞聚集。以上结果提示，α毒素引起的细胞膜CD 11b表达的增加可能是C.产气荚膜梭菌促进血小板-白细胞聚集体的形成，导致由于缺血引起的快速组织坏死。
Gas gangrene caused byClostridium perfringenstype A infection is a highly lethal infection of soft tissue characterized by rapid spread of tissue necrosis. This tissue destruction is related to profound attenuation of blood flow accompanied by formation of platelet-leukocyte aggregates in the blood vessels. Several studies have identified α-toxin, which has both sphingomyelinase and phospholipase C activities, as a major virulence factor in the aggregate formation via activation of the platelet gpIIbIIIa. Here, we show that α-toxin greatly and rapidly increases plasma membrane localization of CD11b, which binds to the platelet gpIIbIIIa via fibrinogen, in mouse neutrophils. Interestingly, short-term treatment of α-toxin has little effect on gene expression profiles in neutrophils, and the toxin does not change the total protein expression levels of CD11b in whole cell lysates. The following analysis demonstrated that CD11b localizes to intracellular vesicles in intact cells, but the localization changed to the cytoplasmic membrane in α-toxin-treated cells. These results suggest that CD11b is recruited to the cytoplasmic membrane by α-toxin. Previously, we reported that α-toxin promotes the formation of ceramide by its sphingomyelinase activity in mouse neutrophils. Interestingly, a synthetic cell-permeable ceramide analog, C2-ceramide, increases plasma membrane localization of CD11b, suggesting that ceramide production by α-toxin recruits CD11b to the cytoplasmic membrane to promote platelet-leukocyte aggregation. Together, our results illustrate that the increase of cell membrane CD11b expression by α-toxin might be crucial for the pathogenesis ofC. perfringensto promote formation of platelet-leukocyte aggregates, leading to rapid tissue necrosis due to ischemia.