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- Title
Immunological consequences of kidney cell death.
- Authors
Sarhan, Maysa; von Mässenhausen, Anne; Hugo, Christian; Oberbauer, Rainer; Linkermann, Andreas
- Abstract
Death of renal cells is central to the pathophysiology of acute tubular necrosis, autoimmunity, necrotizing glomerulonephritis, cystic kidney disease, urosepsis, delayed graft function and transplant rejection. By means of regulated necrosis, immunogenic damage-associated molecular patterns (DAMPs) and highly reactive organelles such as lysosomes, peroxisomes and mitochondria are released from the dying cells, thereby causing an overwhelming immunologic response. The rupture of the plasma membrane exhibits the “point of no return” for the immunogenicity of regulated cell death, explaining why apoptosis, a highly organized cell death subroutine with long-lasting plasma membrane integrity, elicits hardly any immune response. Ferroptosis, an iron-dependent necrotic type cell death, results in the release of DAMPs and large amounts of lipid peroxides. In contrast, anti-inflammatory cytokines are actively released from cells that die by necroptosis, limiting the DAMP-induced immune response to a surrounding microenvironment, whereas at the same time, inflammasome-associated caspases drive maturation of intracellularly expressed interleukin-1β (IL-1β). In a distinct setting, additionally interleukin-18 (IL-18) is expressed during pyroptosis, initiated by gasdermin-mediated plasma membrane rupture. As all of these pathways are druggable, we provide an overview of regulated necrosis in kidney diseases with a focus on immunogenicity and potential therapeutic interventions. Regulated necrosis is a genetically determined process that contributes to acute kidney injury and causes antibody-mediated rejection (ABMR).Necroptosis, ferroptosis and pyroptosis are the best-studied pathways of regulated necrosis in acute kidney injury and transplantation.Necrotic cell death results in the release of DAMPs and is often prone to elicit an immune response.Failure to efficiently remove necrotic debris by LC3-associated phagocytosis (LAP) results in autoimmunity.During the process of kidney transplantation, necrotic cells are capable of priming memory B cells that may drive ABMR years after transplantation.Necroptosis, ferroptosis and pyroptosis can be therapeutically interfered with by small molecules.
- Publication
Cell Death & Disease, 2018, Vol 9, Issue 2, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-017-0057-9