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Visualization of Neutrophil Extracellular Traps in Mesenteric Venules After Mesenteric Ischemia-Reperfusion Injury via Intravital Microscopy
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Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury

Andreas Linkermann1, Jan Hinrich Bräsen, Maurice Darding

  • 1Division of Nephrology and Hypertension and Institute for Pathology, Christian-Albrechts-University, 24105 Kiel, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|July 3, 2013
PubMed

Insights

Regulated necrosis (RN) involves two distinct pathways: cyclophilin D-mediated mitochondrial permeability transition (MPT) and RIPK1-mediated necroptosis. Targeting both pathways offers potential benefits for treating ischemic injury.

Area of Science:

  • Cellular biology
  • Immunology
  • Pathophysiology

Background:

  • Regulated necrosis (RN) can be triggered by cyclophilin D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis.
  • The interplay between these pathways in conditions like ischemia-reperfusion injury (IRI) remains unclear.

Purpose of the Study:

  • To investigate whether cyclophilin D (CypD) and RIPK1 operate in a common RN pathway or distinct pathways.
  • To determine the roles of CypD-mediated MPT and RIPK1-mediated necroptosis in IRI.

Main Methods:

  • Utilized knockout mice deficient in RIPK3 or CypD to study necroptosis and MPT in IRI models.
  • Generated and analyzed CypD-RIPK3 double-deficient mice.
  • Administered RIPK1 and MPT inhibitors (necrostatin-1 and sanglifehrin A) to confirm findings.

Main Results:

  • Mice deficient in RIPK3, a key necroptosis mediator, showed significant protection from IRI.
  • CypD-deficient mice exhibited less protection than RIPK3-deficient mice.
  • CypD-mediated MPT and RIPK1/RIPK3-mediated necroptosis were identified as distinct pathways.
  • CypD-RIPK3 double-deficient mice survived prolonged IRI, which was lethal to single knockouts.

Conclusions:

  • The study demonstrates the coexistence and relevance of two separate RN pathways in IRI: CypD-mediated MPT and RIPK1/RIPK3-mediated necroptosis.
  • Combined therapeutic targeting of these distinct RN pathways may offer a promising strategy for treating ischemic injuries.
Keywords:
RIP1RIP3apoptosisprogrammed necrosis

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