Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury.

Abstract

High levels of inspired oxygen, hyperoxia, are frequently used in patients with acute respiratory failure. Hyperoxia can exacerbate acute respiratory failure, which has high mortality and no specific therapies. We identified novel roles for PTEN-induced putative kinase 1 (PINK1), a mitochondrial protein, and the cytosolic innate immune protein NLRP3 in the lung and endothelium. We generated double knockouts (PINK1(-/-)/NLRP3(-/-)), as well as cell-targeted PINK1 silencing and lung-targeted overexpression constructs, to specifically show that PINK1 mediates cytoprotection in wild-type and NLRP3(-/-) mice. The ability to resist hyperoxia is proportional to PINK1 expression. PINK1(-/-) mice were the most susceptible; wild-type mice, which induced PINK1 after hyperoxia, had intermediate susceptibility; and NLRP3(-/-) mice, which had high basal and hyperoxia-induced PINK1, were the least susceptible. Genetic deletion of PINK1 or PINK1 silencing in the lung endothelium increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis, and oxidant generation.

• Authors: Yi Zhang, Maor Sauler, Amanda S Shinn, Huan Gong, Maria Haslip, Peiying Shan, Praveen Mannam, Patty J Lee
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 11 Pg. 5296-304 (Jun 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24778451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Carrier Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Oxidants
• Protein Kinases
• PTEN-induced putative kinase

Topics

• Animals
• Carrier Proteins (genetics, immunology)
• Endothelium (immunology, pathology)
• Enzyme Induction (drug effects, genetics, immunology)
• Hyperoxia (genetics, immunology, pathology, prevention & control)
• Lung (immunology, pathology)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Oxidants (adverse effects)
• Protein Kinases (genetics, immunology)