Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice

Angela W. Corona, Diana M. Norden, John P. Skendelas, Yan Huang, Jason O'connor, Marcus Lawson, Robert Dantzer, Keith W. Kelley, Jonathan P. Godbout

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

An impaired ability to regulate the activation of microglia by fractalkine (CX3CL1) leads to persistent neuroinflammation and behavioral alterations following lipopolysaccharide (LPS) challenge. While these responses are usually transient, LPS injection caused prolonged depressive-like behavior in fractalkine receptor deficient mice (CX3CR1-/-) that was associated with exaggerated microglial activation and induction of the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent generation of neuroactive kynurenine metabolites may have a pivotal role in the development of depression. Therefore, the purpose of this study was to determine the extent to which LPS-induced depressive-like behavior in CX3CR1-/- mice was dependent on IDO activation. CX3CR1-/- mice were implanted prior to LPS challenge with a slow release pellet of 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO. Here we show that the depressive-like behavior evident in CX3CR1-/- mice 72h after LPS injection was abrogated by inhibition of IDO. LPS also decreased body weight and locomotor activity in CX3CR1-/- mice, but these effects were independent of 1-MT. Consistent with the increased metabolism of TRP by IDO, the ratio of 3-hydroxykynurenine (3-HK) to TRP was increased in the brain 72h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain. The LPS-associated increases in both 3-HK:TRP and 5-HIAA:5-HT ratios were prevented by the inhibition of IDO. Last, IDO blockade attenuated microglial activation in the prefrontal cortex and hippocampus 72h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX3CR1-/- mice.

Original languageEnglish (US)
Pages (from-to)134-142
Number of pages9
JournalBrain, Behavior, and Immunity
Volume31
DOIs
StatePublished - Jul 2013

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Lipopolysaccharides
Tryptophan
Serotonin
Chemokine CX3CL1
Tryptophan Oxygenase
V28 receptor
Inhibition (Psychology)
Kynurenine
Injections
Hydroxyindoleacetic Acid
Aptitude
Brain
Microglia
Locomotion
Prefrontal Cortex
Hippocampus
Body Weight
Depression

Keywords

  • 1-Methyl-tryptophan
  • Depression
  • Fractalkine receptor
  • Indoleamine 2,3-dioxygenase
  • Kynurenine
  • Microglia

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems

Cite this

Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. / Corona, Angela W.; Norden, Diana M.; Skendelas, John P.; Huang, Yan; O'connor, Jason; Lawson, Marcus; Dantzer, Robert; Kelley, Keith W.; Godbout, Jonathan P.

In: Brain, Behavior, and Immunity, Vol. 31, 07.2013, p. 134-142.

Research output: Contribution to journalArticle

Corona, Angela W. ; Norden, Diana M. ; Skendelas, John P. ; Huang, Yan ; O'connor, Jason ; Lawson, Marcus ; Dantzer, Robert ; Kelley, Keith W. ; Godbout, Jonathan P. / Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. In: Brain, Behavior, and Immunity. 2013 ; Vol. 31. pp. 134-142.
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abstract = "An impaired ability to regulate the activation of microglia by fractalkine (CX3CL1) leads to persistent neuroinflammation and behavioral alterations following lipopolysaccharide (LPS) challenge. While these responses are usually transient, LPS injection caused prolonged depressive-like behavior in fractalkine receptor deficient mice (CX3CR1-/-) that was associated with exaggerated microglial activation and induction of the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent generation of neuroactive kynurenine metabolites may have a pivotal role in the development of depression. Therefore, the purpose of this study was to determine the extent to which LPS-induced depressive-like behavior in CX3CR1-/- mice was dependent on IDO activation. CX3CR1-/- mice were implanted prior to LPS challenge with a slow release pellet of 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO. Here we show that the depressive-like behavior evident in CX3CR1-/- mice 72h after LPS injection was abrogated by inhibition of IDO. LPS also decreased body weight and locomotor activity in CX3CR1-/- mice, but these effects were independent of 1-MT. Consistent with the increased metabolism of TRP by IDO, the ratio of 3-hydroxykynurenine (3-HK) to TRP was increased in the brain 72h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain. The LPS-associated increases in both 3-HK:TRP and 5-HIAA:5-HT ratios were prevented by the inhibition of IDO. Last, IDO blockade attenuated microglial activation in the prefrontal cortex and hippocampus 72h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX3CR1-/- mice.",
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