Hato Takashi, Winfree Seth, Kalakeche Rabih, Dube Shataakshi, Kumar Rakesh, Yoshimoto Momoko, Plotkin Zoya, Dagher Pierre C
Departments of Medicine and.
Pediatrics and The Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana.
J Am Soc Nephrol. 2015 Jun;26(6):1347-62. doi: 10.1681/ASN.2014060561. Epub 2014 Nov 14.
Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.
预处理是一种预防性方法，即通过最小化损伤来产生对随后更大剂量相同或甚至不同损伤的保护作用。在免疫细胞中，内毒素预处理可下调炎症反应，同时保留控制感染的能力。然而，在肾脏等器官的组织水平上，预处理的保护机制仍知之甚少。在此，我们表明内毒素预处理在多种体内脓毒症模型中赋予肾上皮细胞保护作用。我们还测试了这样一种假设，即这种保护作用源于内毒素预处理剂量与肾小管之间的直接相互作用。该假设基于我们之前的研究发现，即内毒素对未预处理的肾小管的毒性是直接的，且独立于免疫细胞。值得注意的是，我们发现预处理后的肾小管保护作用绝对需要表达CD14的髓样细胞，尤其是巨噬细胞。此外，完整的巨噬细胞CD14-TRIF信号通路对于肾小管保护至关重要。预处理状态的特征是肾脏内巨噬细胞数量增加和迁移，以及巨噬细胞在S1近端肾小管周围聚集。这些巨噬细胞表现出M2极化增加以及氧化还原和铁处理分子的上调。在肾小管中，预处理可防止过氧化物酶体损伤，并消除S2和S3肾小管的氧化应激和损伤。总之，这些数据表明巨噬细胞是内毒素预处理的重要介质，也是肾组织保护所必需的。因此，预处理是研究脓毒症预防和治疗新保护途径的一个有吸引力的模型。
