Department of Urology, University of Alabama at Birmingham, Birmingham, AL, United States.
Laboratory of Infection Biology and Translational Research, Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
Front Immunol. 2021 Oct 21;12:694865. doi: 10.3389/fimmu.2021.694865. eCollection 2021.
Individuals with calcium oxalate (CaOx) kidney stones can have secondarily infected calculi which may play a role in the development of recurrent urinary tract infection (UTI). Uropathogenic (UPEC) is the most common causative pathogen of UTIs. Macrophages play a critical role in host immune defense against bacterial infections. Our previous study demonstrated that oxalate, an important component of the most common type of kidney stone, impairs monocyte cellular bioenergetics and redox homeostasis. The objective of this study was to investigate whether oxalate compromises macrophage metabolism, redox status, anti-bacterial response, and immune response. Monocytes (THP-1, a human monocytic cell line) were exposed to sodium oxalate (soluble oxalate; 50 µM) for 48 hours prior to being differentiated into macrophages. Macrophages were subsequently exposed to calcium oxalate crystals (50 µM) for 48 hours followed by UPEC (MOI 1:2 or 1:5) for 2 hours. Peritoneal macrophages and bone marrow-derived macrophages (BMDM) from C57BL/6 mice were also exposed to oxalate. THP-1 macrophages treated with oxalate had decreased cellular bioenergetics, mitochondrial complex I and IV activity, and ATP levels compared to control cells. In addition, these cells had a significant increase in mitochondrial and total reactive oxygen species levels, mitochondrial gene expression, and pro-inflammatory cytokine (i.e. Interleukin-1β, IL-1β and Interleukin-6, IL-6) mRNA levels and secretion. In contrast, oxalate significantly decreased the mRNA levels and secretion of the anti-inflammatory cytokine, Interleukin-10 (IL-10). Further, oxalate increased the bacterial burden of primary macrophages. Our findings demonstrate that oxalate compromises macrophage metabolism, redox homeostasis, and cytokine signaling leading to a reduction in anti-bacterial response and increased infection. These data highlight a novel role of oxalate on macrophage function.
个体患有草酸钙 (CaOx) 肾结石，可能会继发感染结石，这可能在复发性尿路感染 (UTI) 的发展中起作用。尿路致病性大肠杆菌 (UPEC) 是 UTIs 最常见的致病病原体。巨噬细胞在宿主免疫防御细菌感染中起着至关重要的作用。我们之前的研究表明，草酸是最常见类型肾结石的重要组成部分，它会损害单核细胞的细胞生物能量和氧化还原稳态。本研究的目的是研究草酸是否会损害巨噬细胞代谢、氧化还原状态、抗细菌反应和免疫反应。单核细胞（THP-1，一种人单核细胞系）在分化为巨噬细胞之前，先用草酸钠（可溶草酸盐；50µM）孵育 48 小时。然后将巨噬细胞暴露于草酸钙晶体（50µM）48 小时，再用尿路致病性大肠杆菌 (MOI 1:2 或 1:5) 孵育 2 小时。还将 C57BL/6 小鼠的腹腔巨噬细胞和骨髓来源的巨噬细胞 (BMDM) 暴露于草酸盐。与对照细胞相比，用草酸盐处理的 THP-1 巨噬细胞的细胞生物能量、线粒体复合物 I 和 IV 活性以及 ATP 水平降低。此外，这些细胞的线粒体和总活性氧水平、线粒体基因表达以及促炎细胞因子（即白细胞介素-1β、IL-1β 和白细胞介素-6、IL-6）mRNA 水平和分泌均显著增加。相比之下，草酸盐显著降低了抗炎细胞因子白细胞介素-10 (IL-10) 的 mRNA 水平和分泌。此外，草酸盐增加了原发性巨噬细胞的细菌负荷。我们的研究结果表明，草酸会损害巨噬细胞代谢、氧化还原稳态和细胞因子信号，导致抗细菌反应降低和感染增加。这些数据突出了草酸对巨噬细胞功能的新作用。
