Origin and Consequences of Necroinflammation

Abstract

When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.

Cell Death Pathways Drive Necroinflammation during Acute Kidney Injury

“…However, the prevention of necroptosis signaling by necrostatins should prevent the release of immune modifying cytokines, but it remains unclear if necrostatins affect CD8+ T-cell cross priming [7]. If RN-pathways specifically shape the immune response, a novel hypothesis emerges and we refer to it as necroinflammation [8]. Box 1 summarizes the most important open questions with respect to necroinflammation during AKI.…”

“…In the concept of necroinflammation, different cell death pathways are immunogenic to a different extent. Whereas apoptosis does not cause and immune response, pathways of regulated necrosis may initiate a detrimental immune cell infiltrate that further deteriorates the primary damage [8]. The second wave of death may also be dependent on necrosis and thereby fuel a vicious circle of necroinflammation [13].…”

Normothermic machine perfusion may prevent regulated cell death following renal ischemia-reperfusion injury

“…Concerning the pathophysiology behind IRI, there was not a discussion of the different regulated (nonapoptotic) cell death pathways in this context, which have been very well investigated over the last few years in murine models. 2,3 The results of these and further studies suggest promising therapeutic targets to prevent renal allograft damage, especially by NMP.…”

“…3 Also, the iron-dependent form of regulated cell death, referred to as ferroptosis, is supposed to induce release of DAMPs following renal IRI. 2 The initial release of DAMPs during the transplantation procedure could trigger future immunological events such as antibody-mediated rejection. 2 However, it is difficult to transfer promising results in murine models of IRI to human disease, especially from murine to human transplantation.…”

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We congratulate DiRito et al 1 on their excellent review, giving an outlook on possible effects of normothermic machine perfusion (NMP) to prevent renal ischemia-reperfusion injury (IRI).Concerning the pathophysiology behind IRI, there was not a discussion of the different regulated (nonapoptotic) cell death pathways in this context, which have been very well investigated over the last few years in murine models. 2,3 The results of these and further studies suggest promising therapeutic targets to prevent renal allograft damage, especially by NMP.Therefore, we would rather focus on regulated cell death following IRI, especially in marginal kidneys after deceased donation. Prolonged warm and cold ischemia times are both associated with reduced long-term allograft survival.

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