Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice |
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| Affiliation: | 1. Department of Neuroscience, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210, USA;2. Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA;3. Department of Animal Science, University of Illinois, 1201 W. Gregory Drive, 250B Edward R. Madigan Laboratory, Urbana, IL 61820, USA;4. Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Dr., Columbus, OH 43210, USA;5. Center for Brain and Spinal Cord Repair, The Ohio State University, 460 W. 12th Ave., Columbus, OH 43210, USA;1. Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA;2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA;3. Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA;4. Facultad de Odontología, Universidad de Costa Rica, San Pedro, San José 11501-2060, Costa Rica;1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine of China Education Ministry, Hefei, Anhui Province, China;2. Anhui Provincial Hospital, Hefei, Anhui Province, China;3. Anhui Provincial Cancer Hospital, Hefei, Anhui Province, China;4. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui Province, China;1. Guy''s King''s and St Thomas'' School of Life Science and Medicine, King''s College London, UK;2. Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK |
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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 72 h 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 72 h 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 72 h 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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