Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI

Abstract

Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis , histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils., ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.

VEGF mitigates histone-induced pyroptosis in the remote liver injury associated with renal allograft ischemia–reperfusion injury in rats

“…recently investigated the role of circulating neutrophil extracellular traps and histones in remote organ injury after warm renal IRI 26. The authors investigated the systemic effects of AKI on remote organs and found that tubular necrosis and neutrophil extracellular trap formation promote kidney injury and remote organ damage due to the systemic release of proinflammatory cytokines and histones.…”

“…Blocking the histone-TLR-4 pathway prevented the hepatic pyroptosis caused by renal allograft IRI. In addition, VEGF was found to mitigate the histone-induced development of pyroptosis and subsequent hepatic inflammation and could serve as a therapeutic target within these pathophysiologic processes.It is interesting to note that Nakazawa et al recently investigated the role of circulating neutrophil extracellular traps and histones in remote organ injury after warm renal IRI 26. The authors investigated the systemic effects of AKI on remote organs and found that tubular necrosis and neutrophil extracellular trap formation promote kidney injury and remote organ damage due to the systemic release of proinflammatory cytokines and histones.…”

Necroptosis in Acute Kidney Injury

“…Indeed, neutrophil necroptosis has also been reported using other triggers, for example, phorbol 12-myristate 13-acetate or crystalline microparticles using neutrophils isolated from Ripk3- ( and Mlkl)- deficient mice [19, 20]. It is likely that neutrophil necroptosis also contributes to other forms of AKI as neutrophils and neutrophil extracellular trap formation has been observed in AKI models involving either glomerular or tubular necrosis [21, 22]. Interestingly, Ripk3 -deficient mice did not display any phenotype in heterologous nephrotoxic nephritis [23], a model induced by an antiserum raised against glomerular antigens with similarities to anti-GBM disease and crescentic glomerulonephritis.…”

A Role of Remote Organs Effect in Acute Kidney Injury Outcome

“…Fur thermore, NETs were detected in lungs only by immunofluorescence staining. NETs inhibition reduced lung injury also suggesting their involvement in lung remote injury after AKI [18].…”