A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

• Published in: The American journal of pathology Vol. 184; no. 7; pp. 2013 - 2022
• Main Authors: Bakker, Pieter J, Butter, Loes M, Claessen, Nike, Teske, Gwendoline J.D, Sutterwala, Fayyaz S, Florquin, Sandrine, Leemans, Jaklien C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014; American Society for Investigative Pathology
• Subjects: Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Apoptosis; Bone Marrow Transplantation; Carrier Proteins - metabolism; Cell Hypoxia; Cell Proliferation; Epithelial Cells - cytology; Interleukin-1beta - metabolism; Kidney Tubules - cytology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Leukocytes - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Pathology; Reperfusion Injury - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2014.04.005

Ischemia/reperfusion injury is a major cause of acute kidney injury. Improving renal repair would represent a therapeutic strategy to prevent renal dysfunction. The innate immune receptor Nlrp3 is involved in tissue injury, inflammation, and fibrosis; however, its role in repair after ischemia/reperfusion is unknown. We address the role of Nlrp3 in the repair phase of renal ischemia/reperfusion and investigate the relative contribution of leukocyte- versus renal-associated Nlrp3 by studying bone marrow chimeric mice. We found that Nlrp3 expression was most profound during the repair phase. Although Nlrp3 expression was primarily expressed by leukocytes, both leukocyte- and renal-associated Nlrp3 was detrimental to renal function after ischemia/reperfusion. The Nlrp3-dependent cytokine IL-1β remained unchanged in kidneys of all mice. Leukocyte-associated Nlrp3 negatively affected tubular apoptosis in mice that lacked Nlrp3 expression on leukocytes, which correlated with reduced macrophage influx. Nlrp3-deficient ( Nlrp3KO ) mice with wild-type bone marrow showed an improved repair response, as seen by a profound increase in proliferating tubular epithelium, which coincided with increased hepatocyte growth factor expression. In addition, Nlrp3KO tubular epithelial cells had an increased repair response in vitro , as seen by an increased ability of an epithelial monolayer to restore its structural integrity. In conclusion, Nlrp3 shows a tissue-specific role in which leukocyte-associated Nlrp3 is associated with tubular apoptosis, whereas renal-associated Nlrp3 impaired wound healing.