Eisenbarth Stephanie C, Colegio Oscar R, O'Connor William, Sutterwala Fayyaz S, Flavell Richard A
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2008 Jun 19;453(7198):1122-6. doi: 10.1038/nature06939. Epub 2008 May 21.
Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.
铝佐剂，通常被称为“明矾”，是全球人类和动物疫苗中最常用的佐剂，然而明矾刺激免疫系统的潜在机制仍然未知。Toll样受体在感知感染方面至关重要，因此是免疫研究中各种佐剂的常见靶点。虽然已知明矾在体外可诱导促炎细胞因子的产生，但反复证明明矾激活免疫系统并不需要完整的Toll样受体信号传导。在此我们表明，铝佐剂可激活一种称为Nalp3（也称为冷吡啉、CIAS1或NLRP3）炎性小体的细胞内固有免疫反应系统。巨噬细胞在体外对明矾产生促炎细胞因子白细胞介素-1β和白细胞介素-18需要完整的炎性小体信号传导。此外，在体内，缺乏Nalp3、ASC（含半胱天冬酶募集结构域的凋亡相关斑点样蛋白）或半胱天冬酶-1的小鼠，对与铝佐剂一起施用的抗原未能产生显著的抗体反应，而对完全弗氏佐剂的反应则保持完好。我们确定Nalp3炎性小体是铝佐剂佐剂效应中的关键要素；此外，我们表明固有炎性小体途径可指导体液适应性免疫反应。这可能会影响我们未来设计有效但安全的佐剂的方式。
