The macrophage mediates the renoprotective effects of endotoxin preconditioning.
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.
Departments of Medicine and.
Takashi
T
Hato
Departments of Medicine and.
Seth
S
Winfree
Departments of Medicine and.
Rabih
R
Kalakeche
Departments of Medicine and.
Shataakshi
S
Dube
Departments of Medicine and.
Rakesh
R
Kumar
Pediatrics and The Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana.
Momoko
M
Yoshimoto
Departments of Medicine and.
Zoya
Z
Plotkin
Departments of Medicine and pdaghe2@iupui.edu.
Pierre C
PC
Dagher
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins / Q000378:metabolism* / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
acute renal failure; macrophages; proximal tubule; reactive oxygen species; renal epithelial cell