Nonaka Saori, Ando Yuki, Kanetani Takuto, Hoshi Chiharu, Nakai Yuji, Nainu Firzan, Nagaosa Kaz, Shiratsuchi Akiko, Nakanishi Yoshinobu
From the Graduate School of Medical Sciences and.
School of Pharmacy, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
J Biol Chem. 2017 May 12;292(19):8059-8072. doi: 10.1074/jbc.M116.769745. Epub 2017 Mar 21.
The phagocytic elimination of cells undergoing apoptosis is an evolutionarily conserved innate immune mechanism for eliminating unnecessary cells. Previous studies showed an increase in the level of engulfment receptors in phagocytes after the phagocytosis of apoptotic cells, which leads to the enhancement of their phagocytic activity. However, precise mechanisms underlying this phenomenon require further clarification. We found that the pre-incubation of a phagocyte cell line with the fragments of apoptotic cells enhanced the subsequent phagocytosis of apoptotic cells, accompanied by an augmented expression of the engulfment receptors Draper and integrin αPS3. The DNA-binding activity of the transcription repressor Tailless was transiently raised in those phagocytes, depending on two partially overlapping signal-transduction pathways for the induction of phagocytosis as well as the occurrence of engulfment. The RNAi knockdown of in phagocytes abrogated the enhancement of both phagocytosis and engulfment receptor expression. Furthermore, the hemocyte-specific RNAi of reduced apoptotic cell clearance in embryos. Taken together, we propose the following mechanism for the activation of phagocytes after an encounter with apoptotic cells: two partially overlapping signal-transduction pathways for phagocytosis are initiated; transcription repressor Tailless is activated; expression of engulfment receptors is stimulated; and phagocytic activity is enhanced. This phenomenon most likely ensures the phagocytic elimination of apoptotic cells by stimulated phagocytes and is thus considered as a mechanism to prime phagocytes in innate immunity.
对正在经历凋亡的细胞进行吞噬清除是一种进化上保守的先天性免疫机制，用于清除不必要的细胞。先前的研究表明，吞噬细胞在吞噬凋亡细胞后，其吞噬受体水平会升高，这导致其吞噬活性增强。然而，这一现象背后的确切机制仍需进一步阐明。我们发现，用凋亡细胞碎片对吞噬细胞系进行预孵育可增强随后对凋亡细胞的吞噬作用，并伴有吞噬受体Draper和整合素αPS3表达的增加。转录抑制因子无尾（Tailless）的DNA结合活性在这些吞噬细胞中短暂升高，这取决于两条部分重叠的信号转导途径，一条用于诱导吞噬作用，另一条用于吞噬的发生。在吞噬细胞中通过RNA干扰敲低（相关基因）可消除吞噬作用和吞噬受体表达的增强。此外，在血细胞中特异性敲低（相关基因）会减少果蝇胚胎中凋亡细胞的清除。综上所述，我们提出了吞噬细胞在遇到凋亡细胞后被激活的以下机制：启动两条部分重叠的吞噬信号转导途径；激活转录抑制因子无尾；刺激吞噬受体的表达；增强吞噬活性。这种现象很可能确保了被刺激的吞噬细胞对凋亡细胞的吞噬清除，因此被认为是先天性免疫中使吞噬细胞致敏的一种机制。
