Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
J Immunol. 2012 Aug 1;189(3):1459-66. doi: 10.4049/jimmunol.1200484. Epub 2012 Jun 25.
Autophagy is an important mechanism used by macrophages to kill intracellular pathogens. The results reported in this study demonstrate that autophagy is also involved in the macrophage killing of the extracellular enteropathogen Citrobacter rodentium after phagocytosis. The process was significantly impaired in macrophages isolated from mice chronically infected with the helminth parasite Heligmosomoides polygyrus. The H. polygyrus-mediated inhibition of autophagy was Th2 dependent because it was not observed in macrophages isolated from helminth-infected STAT6-deficient mice. Moreover, autophagy of Citrobacter was inhibited by treating macrophages with IL-4 and IL-13. The effect of H. polygyrus on autophagy was associated with decreased expression and processing of L chain protein 3 (LC3), a key component of the autophagic machinery. The helminth-induced inhibition of LC3 expression and processing was STAT6 dependent and could be recapitulated by treatment of macrophages with IL-4 and IL-13. Knockdown of LC3 significantly inhibited autophagic killing of Citrobacter, attesting to the functional importance of the H. polygyrus-mediated downregulation of this process. These observations reveal a new aspect of the immunosuppressive effects of helminth infection and provide mechanistic insights into our earlier finding that H. polygyrus significantly worsens the in vivo course of Citrobacter infection.
自噬是巨噬细胞杀死细胞内病原体的一种重要机制。本研究的结果表明，自噬也参与了吞噬细胞对细胞外肠道病原体柠檬酸杆菌的杀伤。从慢性感染蠕虫寄生虫旋毛虫的小鼠中分离出的巨噬细胞中，自噬过程明显受损。旋毛虫介导的自噬抑制是 Th2 依赖性的，因为在从感染蠕虫的 STAT6 缺陷型小鼠中分离出的巨噬细胞中没有观察到这种现象。此外，用 IL-4 和 IL-13 处理巨噬细胞可抑制柠檬酸杆菌的自噬。旋毛虫对自噬的影响与 L 链蛋白 3 (LC3)的表达和加工减少有关，LC3 是自噬机制的关键组成部分。LC3 的表达和加工受 STAT6 依赖的抑制，用 IL-4 和 IL-13 处理巨噬细胞可重现这种抑制。LC3 的敲低显著抑制了柠檬酸杆菌的自噬杀伤作用，证明了旋毛虫介导的这一过程下调的功能重要性。这些观察结果揭示了蠕虫感染的免疫抑制作用的一个新方面，并为我们之前的发现提供了机制上的见解，即旋毛虫显著加重了柠檬酸杆菌感染的体内过程。
