Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury

Raghu Kempegowda Tadagavadi, Weiwei Wang, Ganesan Ramesh

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Overwhelming evidence suggests that ischemia-reperfusion injury of the kidney is an inflammatory disease mediated by innate and adoptive immune systems. The neuronal guidance molecule netrin-1 was shown to modulate inflammatory responses. Given that ischemic kidney is particularly prone to reperfusion-elicited inflammation, we sought to determine the function of netrin-1 and its receptor UNC5B in ischemia-reperfusion-induced inflammation. Renal ischemia-reperfusion caused a rapid decrease in serum netrin-1 levels. Administration of recombinant netrin-1 before or after renal ischemia-reperfusion reduced kidney injury, apoptosis, monocyte and neutrophil infiltration, and cytokine (IL-6, IL-1β, and TNF-α) and chemokine (MCP-1, macrophage-derived cytokine, monokine-induced IFN-γ, keratinocyte-derived chemokine, and chemokine with 6 cysteines) production. Analysis for different netrin-1 receptors on leukocytes showed very high expression of UNC5B but not UNC5C, UNC5D, neogenin, or deleted in colorectal cancer. Expression of UNC5A was low. Neutralization of UNC5B receptor reduced netrin-1-mediated protection against renal ischemia-reperfusion injury, and it increased monocyte and neutrophil infiltration, as well as serum and renal cytokine and chemokine production, with increased kidney injury and renal tubular cell apoptosis. Finally, investigation into netrin-1's effect on CD4 T cell stimulation showed suppression of Th1/Th2/Th17 cytokine (IL-2, IL-6, IL-10, IL-13, IL-17, IFN-γ, IL-4, and TNF-α) production in vitro. Our studies demonstrate that netrin-1 acting through UNC5B receptor reduces renal ischemia-reperfusion injury and its associated renal inflammation.

Original languageEnglish (US)
Pages (from-to)3750-3758
Number of pages9
JournalJournal of Immunology
Volume185
Issue number6
DOIs
StatePublished - Sep 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury'. Together they form a unique fingerprint.

  • Cite this