Laboratory of Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
Immunity. 2011 Jul 22;35(1):34-44. doi: 10.1016/j.immuni.2011.04.015. Epub 2011 Jun 16.
Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1β production, thereby compromising antimicrobial immunity.
膜相关和细胞质模式识别受体对微生物成分的检测是先天免疫的本质，导致保护性宿主反应的激活。然而，目前尚不清楚免疫细胞如何特异性地对致病菌作出反应。我们使用炭疽杆菌的毒性和非毒性菌株表明，受感染的巨噬细胞中 ATP 的分泌以及随后 P2X7 嘌呤能受体和核苷酸结合寡聚结构域（NOD）样受体的激活对于 IL-1 依赖性宿主对毒性炭疽杆菌的保护至关重要。重要的是，毒性炭疽杆菌产生的致死毒素阻断了蛋白激酶 p38 MAPK 和 AKT 的激活，导致缝隙连接 ATP 释放通道的打开和巨噬细胞死亡的诱导。通过组成型 p38 或 AKT 激活来预防细胞死亡或 ATP 释放会干扰炎性小体的激活和 IL-1β 的产生，从而损害抗菌免疫。
