Toll-Like Receptors and Danger Signaling in Kidney Injury

Anders, Hans‐Joachim

doi:10.1681/asn.2010030233

Cited by 124 publications

(120 citation statements)

References 39 publications

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“…7 This explains why, for example, gouty arthritis is clinically indistinguishable from bacterial arthritis. 4,19,20 Together, this suggests that necroinflammation is an autoamplification loop of necrosis and inflammation that evolved as a life-saving mechanism of host defense but causes unnecessary tissue damage in sterile diseases.…”

Section: What Is Necroinflammation?mentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

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203

185

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The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.

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Section: What Is Necroinflammation?mentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

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203

185

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“…13 Our work reported here is based on the assumption that additional intracellular molecules that can act as DAMPs and sense renal tissue damage to the immune system remain to be discovered. 14 Histones are a group of nuclear proteins that form heterooctamers to wind up the double-stranded DNA to form chromatin as well as chromosomes. Histones are released from dying neutrophils during bacterial infections for host defense, the so-called neutrophil extracellular traps (NETs).…”

mentioning

confidence: 99%

Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

Allam

Scherbaum

Darisipudi

et al. 2012

Journal of the American Society of Nephrology

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377

369

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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-kB, 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.

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“…26 Toll-like receptors (TLRs) are a class of proteins that play an important role in alerting the innate immune system. 27,28 They are single membrane-spanning noncatalytic receptors that recognize structurally conserved molecules derived from invading pathogens. TLR-4 appears to play a key inflammatory role in AKI.…”

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confidence: 99%