Baruah Paramita, Dumitriu Ingrid E, Peri Giuseppe, Russo Vincenzo, Mantovani Alberto, Manfredi Angelo A, Rovere-Querini Patrizia
Clinical Immunology Unit, H. San Raffaele Scientific Institute, via Olgettina 58, Milano 20132, Italy.
J Leukoc Biol. 2006 Jul;80(1):87-95. doi: 10.1189/jlb.0805445. Epub 2006 Apr 14.
Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 (MART-1) tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.
五聚体蛋白（PTX）和补体属于先天性免疫系统的体液部分，在抵御微生物的免疫防御以及清除细胞碎片方面具有重要功能。典型的长链五聚体蛋白PTX3和经典补体途径的第一成分C1q是先天性调理素，参与吞噬细胞对死亡细胞的清除。各种先天性调理素之间的相互作用是否会影响其功能尚未完全明确。我们在此表明，特定的Toll样受体（TLR）配体可诱导未成熟树突状细胞（DC）产生C1q和PTX3。此外，这些分子以相似的动力学与死亡细胞结合，尽管它们识别细胞膜上不同的结构域。PTX3在液相中与C1q结合，减少C1q在凋亡细胞上的沉积及随后的补体激活。在存在TLR4配体和凋亡细胞的情况下，C1q可增加DC对凋亡细胞的吞噬作用以及白细胞介素-12的释放；PTX3则抑制这两个过程。此外，即使存在C1q，PTX3也能抑制死亡细胞表达的MELAN-A/黑色素瘤抗原反应性T细胞1（MART-1）肿瘤抗原的交叉呈递。这些结果表明，C1q和PTX3的相互作用会影响DC对凋亡细胞的清除。C1q和PTX3由初级促炎信号协同诱导，且在炎症过程中相互调节，这影响了抗原呈递细胞对凋亡细胞的清除，可能在免疫稳态中发挥作用。
