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

77 Citations (Scopus)

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

Fingerprint

Reperfusion Injury
Cytokines
Inflammation
Kidney
Reperfusion
Chemokines
Ischemia
Neutrophil Infiltration
Monocytes
Interleukin-6
netrin-1
Monokines
Apoptosis
Interleukin-13
Interleukin-17
Wounds and Injuries
Serum
Interleukin-1
Interleukin-4
Interleukin-10

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. / Tadagavadi, Raghu Kempegowda; Wang, Weiwei; Ramesh, Ganesan.

In: Journal of Immunology, Vol. 185, No. 6, 15.09.2010, p. 3750-3758.

Research output: Contribution to journalArticle

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