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Review
. 2016 Jan;27(1):27-39.
doi: 10.1681/ASN.2015040405. Epub 2015 Sep 2.

Necroinflammation in Kidney Disease

Shrikant R Mulay  1 , Andreas Linkermann  2 , Hans-Joachim Anders  3
Affiliations
Review

Necroinflammation in Kidney Disease

Shrikant R Mulay et al. J Am Soc Nephrol. 2016 Jan.

Abstract

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.

Keywords: Immunology and pathology; acute renal failure; kidney failure.

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Figures

Figure 1.
Figure 1.
Molecular pathways involved in necroinflammation. Necrotic renal cells release DAMPs and alarmins that activate DAMP or alarmin receptors on immune (and parenchymal) cells, respectively (Table 1). Activation of immune (and parenchymal) cells induces the secretion of numerous proinflammatory cytokines that in turn can induce several forms of regulated necrosis (e.g., necroptosis, pyroptosis). The necroptosis signaling pathway involves auto- and transphosphorylation of RIPK1 and RIPK3 and the recruitment of MLKL. Activation of caspase-1 induces release of IL-1β and IL-18, which causes inflammation. Certain DAMPs and proinflammatory cytokines, such as TNF-α or IL-8, directly activate neutrophils for the formation of NETs. NET formation expels large amounts of histones into the extracellular space. Extracellular histones have direct cytotoxic impact on renal cells and in addition induce TLR2-/TLR4- and NLRP3-related immune cell activation. GPX-4, glutathione peroxidase; MOMP, mitochondrial outer membrane permeabilization; p-MLKL, phospho-mixed lineage kinase domain-like; Ripk1, receptor-activating protein kinase 1; Ripk3, receptor-activating protein kinase 3.
Figure 2.
Figure 2.
Necroinflammation in glomerular and tubulointerstitial inflammation. (A) Neutrophil extracellular trap formation in glomerular capillaries (e.g., in ANCA vasculitis) causes histone-related endothelial cell death and subsequent capillary loop necrosis. DAMP release activates other glomerular cells to produce cytokines and chemokines, which recruit more cytokine-producing leukocytes, including neutrophils undergoing NETosis. TNF-α and histones drive further necrosis of glomerular cells. The associated rupture of the glomerular basement membrane implies not only podocyte injury but also plasma leakage into Bowman’s space. Plasma components such as fibrinogen activate parietal epithelial cell hyperplasia and crescent formation. (B) In tubule injury, regulated necrosis of any kind may be the initial event. Histones released by tubular cells and netting neutrophils elicit direct cytotoxicity. The associated release of DAMPs and alarmins induces inflammation, which implies the recruitment of cytokine-producing leukocytes into the peritubular interstitium. Also, TNF-α and possibly other cytokines drive necroptosis as a secondary cell death category contributing to tubular necrosis and renal dysfunction. This sets up the auto-amplification loop of necroinflammation.
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