Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior
While the relationship between inflammation and depression is well-established, the molecular mechanisms mediating this relationship remain unclear. RNA sequencing analysis comparing brains of vehicle- and lipopolysaccharide-treated mice revealed LCN2 among the most dysregulated genes. As LCN2 is known to be an important regulator of the immune response to bacterial infection, we investigated its role in the behavioral response to lipopolysaccharide.
To explore the role of LCN2 in modulating behavior following lipopolysaccharide administration using wild type (WT) and lcn2−/− mice.
Using a within-subjects design, mice were treated with 0.33 mg/kg liposaccharide (LPS) and vehicle. Primary outcome measures included body weight, food consumption, voluntary wheel running, sucrose preference, and the tail suspension test. To evaluate the inflammatory response, 1 week later, mice were re-administered either vehicle or LPS and terminated at 6 h.
While lcn2−/− mice had increased baseline food consumption and body weight, they showed a pattern of reduced food consumption and weight loss similar to WT mice in response to LPS. WT and lcn2−/− mice both recovered voluntary activity on the fourth day following LPS. LPS induced equivalent reductions in sucrose preference and TST immobility in the WT and lcn2−/− mice. Finally, there were no significant effects of genotype on inflammatory markers.
Our data demonstrate that lcn2 is dispensable for sterile inflammation-induced sickness and depression-like behavior. Specifically, lcn2−/− mice displayed sickness and immobility in the tail suspension test comparable to that of WT mice both in terms of intensity and duration.
KeywordsLipocalin-2 Inflammation Lipopolysaccharide Innate immunity Depression Sickness behavior
This research was supported by the National Institutes of Health (R01 CA193522 and R21 MH104694 to R.D., R01 NS073939 to A.K., R.D., and C.J.H., and an MD Anderson Cancer Center Support Grant (P30 CA016672)).
Compliance with ethical standards
All protocols were approved by the University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.
Conflict of interest
Robert Dantzer has received honoraria from Danone Nutricia Research and Pfizer that are unrelated to the present study. All remaining authors declare no competing interests.
- Can A, Dao DT, Terrillion CE, Piantadosi SC, Bhat S, Gould TD (2012) The tail suspension test. J Vis Exp (59):e3769. https://doi.org/10.3791/3769(2012)
- Cleaver JO, You D, Michaud DR, Guzmán Pruneda FA, Leiva Juarez MM, Zhang J, Weill PM, Adachi R, Gong L, Moghaddam S, Poynter ME, Tuvim MJ, Evans SE (2014) Lung epithelial cells are essential effectors of inducible resistance to pneumonia. Mucosal Immunol 7:78–88. https://doi.org/10.1038/mi.2013.26 CrossRefPubMedGoogle Scholar
- Frenois F, Moreau M, O’Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531CrossRefPubMedPubMedCentralGoogle Scholar
- Moreau M, Andre C, O’Connor JC, Dumich SA, Woods JA, Kelley KW, Dantzer R, Lestage J, Castanon N (2008) Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior. Brain Behav Immun 22:1087–1095CrossRefPubMedPubMedCentralGoogle Scholar
- Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, Huang Y, Zong H, Friedman RA, Barasch J, Lanzano P, Deng L, Leibel RL, Rubin M, Nickolas T, Chung W, Zeltser LM, Williams KW, Pessin JE, Kousteni S (2017) MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543:385–390CrossRefPubMedPubMedCentralGoogle Scholar
- Ostvik AE, Granlund AV, Torp SH, Flatberg A, Beisvag V, Waldum HL, Flo TH, Espevik T, Damas JK, Sandvik AK (2013) Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2. Clin Exp Immunol 173:502–511CrossRefPubMedPubMedCentralGoogle Scholar
- Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41CrossRefPubMedPubMedCentralGoogle Scholar
- Teixeira S, Machado S, Velasques B, Sanfim A, Minc D, Peressutti C, Bittencourt J, Budde H, Cagy M, Anghinah R, Basile LF, Piedade R, Ribeiro P, Diniz C, Cartier C, Gongora M, Silva F, Manaia F, Silva JG (2014) Integrative parietal cortex processes: neurological and psychiatric aspects. J Neurol Sci 338:12–22CrossRefGoogle Scholar