Table_1_Cytotoxic Necrotizing Factor 1 Downregulates CD36 Transcription in Macrophages to Induce Inflammation During Acute Urinary Tract Infections.docx

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) induce cystitis, pyelonephritis, and can cause kidney scarring and failure if inflammation is not under control. The detailed effects of cytotoxic necrotizing factor 1 (CNF1), the key UPEC toxin, on the pathogenicity of UPEC remain unclear. CD36 is an important scavenger receptor, responsible for pathogen and apoptotic cell clearance, and plays an essential role in host immune defense and homeostasis. Regulation of CD36 by bacterial toxins has not been reported. In this study, using a pyelonephritis mouse model, CNF1 was observed to contribute to increasing neutrophils and bacterial titers in infected bladder and kidney tissues, resulting in severe inflammation and tissue damage. CD36 expression in macrophages was found to be decreased by CNF1 in vitro and in vivo. We demonstrated that CNF1 attenuated CD36 transcription by decreasing expressions of its upstream transcription factors LXRβ and C/EBPα and their recruitment to the CD36 promotor. In addition, Cdc42 was found to be involved in CNF1-mediated downregulation of LXRβ. Our study investigated the pathogenesis of cnf1-carrying UPEC, which affected host innate immune defenses and homeostasis through regulation of CD36 in macrophages during acute UTIs.

尿路致病性大肠埃希菌（uropathogenic Escherichia coli, UPEC）引发的尿路感染（Urinary tract infections, UTIs）可诱发膀胱炎、肾盂肾炎；若炎症未能得到有效控制，还可造成肾脏瘢痕形成与肾功能衰竭。作为UPEC的关键毒素，细胞毒性坏死因子1（cytotoxic necrotizing factor 1, CNF1）对UPEC致病力的具体调控机制仍有待阐明。CD36是一类重要的清道夫受体（scavenger receptor），可介导病原体与凋亡细胞的清除，在宿主免疫防御及内环境稳态维持中发挥核心作用。目前尚无细菌毒素调控CD36表达的相关研究报道。本研究借助肾盂肾炎小鼠模型，观察到CNF1可增加感染膀胱与肾脏组织内的中性粒细胞数量及细菌载量，进而诱发严重炎症反应与组织损伤。体内外实验均证实，CNF1可下调巨噬细胞中CD36的表达水平。本研究进一步证实，CNF1通过降低CD36的上游转录因子LXRβ与C/EBPα的表达，并减少二者向CD36启动子的募集，从而抑制CD36的转录活性。此外，研究发现Cdc42参与了CNF1介导的LXRβ下调过程。本研究揭示了携带CNF1的UPEC的致病机制：在急性尿路感染过程中，该病原菌通过调控巨噬细胞内CD36的表达，干扰宿主先天免疫防御与内环境稳态。