Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.
In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Pettenkoferstr. 8a, D-80336 Munich, Germany.
Ramanjaneyulu
R
Allam
Christina Rebecca
CR
Scherbaum
Murthy Narayana
MN
Darisipudi
Shrikant R
SR
Mulay
Holger
H
Hägele
Julia
J
Lichtnekert
Jan Henrik
JH
Hagemann
Khader Valli
KV
Rupanagudi
Mi
M
Ryu
Claudia
C
Schwarzenberger
Bernd
B
Hohenstein
Christian
C
Hugo
Bernd
B
Uhl
Christoph A
CA
Reichel
Fritz
F
Krombach
Marc
M
Monestier
Helen
H
Liapis
Kristin
K
Moreth
Liliana
L
Schaefer
Hans-Joachim
HJ
Anders
D058186:Acute Kidney Injury / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D007269:Injections, Intra-Arterial; D007668:Kidney / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009336:Necrosis; D012077:Renal Artery; D015427:Reperfusion Injury / Q000517:prevention & control; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D006657:Histones; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4