Symington J W, Wang C, Twentyman J, Owusu-Boaitey N, Schwendener R, Núñez G, Schilling J D, Mysorekar I U
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
Laboratory of Liposome Research, Institute of Molecular Cancer Research, Zurich, Switzerland.
Mucosal Immunol. 2015 Nov;8(6):1388-99. doi: 10.1038/mi.2015.7. Epub 2015 Feb 11.
Urinary tract infections (UTIs) are frequent, commonly recurrent, and costly. Deficiency in a key autophagy protein, ATG16L1, protects mice from infection with the predominant bacterial cause of UTIs, Uropathogenic E. coli (UPEC). Here, we report that loss of ATG16L1 in macrophages accounts for this protective phenotype. Compared with wild-type macrophages, macrophages deficient in ATG16L1 exhibit increased uptake of UPEC and enhanced secretion of interleukin-1β (IL-1β). The increased IL-1β production is dependent upon activation of the NLRP3 inflammasome and caspase-1. IL-1β secretion was also enhanced during UPEC infection of ATG16L1-deficient mice in vivo, and inhibition of IL-1β signaling abrogates the ATG16L1-dependent protection from UTIs. Our results argue that ATG16L1 normally suppresses a host-protective IL-1β response to UPEC by macrophages.
尿路感染（UTIs）很常见，通常会复发，且成本高昂。关键自噬蛋白ATG16L1的缺陷可保护小鼠免受尿路感染的主要细菌病原体——尿路致病性大肠杆菌（UPEC）的感染。在此，我们报告巨噬细胞中ATG16L1的缺失导致了这种保护表型。与野生型巨噬细胞相比，缺乏ATG16L1的巨噬细胞对UPEC的摄取增加，白细胞介素-1β（IL-1β）的分泌增强。IL-1β产生的增加依赖于NLRP3炎性小体和半胱天冬酶-1的激活。在体内UPEC感染ATG16L1缺陷小鼠的过程中，IL-1β的分泌也增强了，并且抑制IL-1β信号传导可消除ATG16L1依赖性的尿路感染保护作用。我们的结果表明，ATG16L1通常会抑制巨噬细胞对UPEC的宿主保护性IL-1β反应。
