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NTPDase8 Protects Against Liver Ischemia-Reperfusion Injury in Mice
Taha Kelestemur1, Simon C Robson2, Zoltán H Németh1,3
1Department of Anesthesiology, Columbia University, New York, New York, USA.
Summary
NTPDase8, primarily on liver cells, protects against liver injury from ischemia-reperfusion and shock. Its absence increases liver damage by altering purinergic signaling.
Area of Science:
- Biochemistry
- Immunology
- Hepatology
Background:
- Nucleoside triphosphate diphosphohydrolases (NTPDases) regulate purinergic signaling by controlling extracellular purine levels.
- Purinergic signaling is implicated in liver ischemia-reperfusion (I/R) injury, with CD39 (NTPDase1) showing protective effects.
- The roles of other NTPDase family members, specifically NTPDase2, NTPDase3, and NTPDase8, in liver I/R injury remain largely unknown.
Purpose of the Study:
- To investigate the roles of NTPDase2, NTPDase3, and NTPDase8 in liver injury.
- To determine the cellular source of NTPDase8's protective effect in the liver.
- To elucidate the mechanisms by which NTPDase8 influences liver injury, including its impact on purinergic signaling.
Main Methods:
- Generation and use of global knockout mice for Entpd2, Entpd3, and Entpd8.
- Induction of liver I/R injury and evaluation of liver damage.
- Induction of global ischemia via hemorrhagic shock and resuscitation in wild-type and Entpd8 knockout mice.
- Construction of bone marrow chimeric mice to assess the role of hematopoietic cell-derived NTPDases.
- Single-nucleus RNA sequencing to identify NTPDase8-expressing cell types in the liver.
- Measurement of extracellular ATP concentrations.
- Administration of P2 receptor antagonist (suramin) to assess the role of P2 signaling.
Main Results:
- While Entpd2-/- and Entpd3-/- mice showed no significant difference in liver injury compared to wild-type (WT) mice after I/R, Entpd8-/- mice exhibited significantly increased liver injury.
- Bone marrow chimeric studies revealed that NTPDase8 expressed on parenchymal liver cells, predominantly hepatocytes, confers protection against hepatic injury.
- Entpd8-/- mice displayed elevated ATP levels in the liver and plasma post-I/R injury.
- Treatment with suramin reduced liver injury in Entpd8-/- mice, indicating a contribution of P2 receptor signaling.
- Entpd8-/- mice also showed exacerbated liver injury following hemorrhagic shock and resuscitation compared to WT mice.
Conclusions:
- NTPDase8 plays a critical protective role in the liver during I/R injury and hemorrhagic shock.
- Hepatocyte-expressed NTPDase8 is a key regulator suppressing inflammatory and metabolic responses to hepatic insults.
- Differential roles of NTPDase family members exist in the liver, with NTPDase8 being a crucial suppressor of injury, independent of vascular NTPDase1.
