Tauroursodeoxycholic acid reduces glial cell activation in an animal model of acute neuroinflammation

Journal of Neuroinflammation

Lorenzo Romero-Ramírez²  Manuel Nieto-Sampedro²  M Asunción Barreda-Manso²  Natalia Yanguas-Casás¹ 

[1] Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain;Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain

关键词: Vascular cell adhesion molecule 1;    Protein kinase RNA-activated;    NFκB;    Monocyte chemotactic protein-1;    Migration;    Microglia;    Lipopolysaccharide;    Inducible nitric oxide synthase;    Bile salts;    Astrocytes;   

Others  :  815213
DOI  :  10.1186/1742-2094-11-50

 received in 2013-09-06, accepted in 2014-02-28,  发布年份 2014

【 摘 要 】

Background

Bile acids are steroid acids found predominantly in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in different animal models of stroke and neurological diseases. However, the anti-inflammatory properties of TUDCA in the central nervous system (CNS) remain unknown.

Methods

The acute neuroinflammation model of intracerebroventricular (icv) injection with bacterial lipopolysaccharide (LPS) in C57BL/6 adult mice was used herein. Immunoreactivity against Iba-1, GFAP, and VCAM-1 was measured in coronal sections in the mice hippocampus. Primary cultures of microglial cells and astrocytes were obtained from neonatal Wistar rats. Glial cells were treated with proinflammatory stimuli to determine the effect of TUDCA on nitrite production and activation of inducible enzyme nitric oxide synthase (iNOS) and NFκB luciferase reporters. We studied the effect of TUDCA on transcriptional induction of iNOS and monocyte chemotactic protein-1 (MCP-1) mRNA as well as induction of protein expression and phosphorylation of different proteins from the NFκB pathway.

Results

TUDCA specifically reduces microglial reactivity in the hippocampus of mice treated by icv injection of LPS. TUDCA treatment reduced the production of nitrites by microglial cells and astrocytes induced by proinflammatory stimuli that led to transcriptional and translational diminution of the iNOS. This effect might be due to inhibition of the NFκB pathway, activated by proinflammatory stimuli. TUDCA decreased in vitro microglial migration induced by both IFN-γ and astrocytes treated with LPS plus IFN-γ. TUDCA inhibition of MCP-1 expression induced by proinflammatory stimuli could be in part responsible for this effect. VCAM-1 inmunoreactivity in the hippocampus of animals treated by icv LPS was reduced by TUDCA treatment, compared to animals treated with LPS alone.

Conclusions

We show a triple anti-inflammatory effect of TUDCA on glial cells: i) reduced glial cell activation, ii) reduced microglial cell migratory capacity, and iii) reduced expression of chemoattractants (e.g., MCP-1) and vascular adhesion proteins (e.g., VCAM-1) required for microglial migration and blood monocyte invasion to the CNS inflammation site. Our results present a novel TUDCA anti-inflammatory mechanism, with therapeutic implications for inflammatory CNS diseases.

【 授权许可】

   
2014 Yanguas-Casás et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Dong Y, Benveniste EN: Immune function of astrocytes. Glia 2001, 36:180-190.
• [2]Aloisi F: Immune function of microglia. Glia 2001, 36:165-179.
• [3]Allan SM, Rothwell NJ: Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 2003, 358:1669-1677.
• [4]Lucas SM, Rothwell NJ, Gibson RM: The role of inflammation in CNS injury and disease. Br J Pharmacol 2006, 147(Suppl 1):S232-S240.
• [5]Aloisi F, Ambrosini E, Columba-Cabezas S, Magliozzi R, Serafini B: Intracerebral regulation of immune responses. Ann Med 2001, 33:510-515.
• [6]Hausmann ON: Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003, 41:369-378.
• [7]Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM: The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 2002, 61:623-633.
• [8]McGeer PL, McGeer EG: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995, 21:195-218.
• [9]Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease – a double-edged sword. Neuron 2002, 35:419-432.
• [10]Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999, 22:391-397.
• [11]Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T: Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care 2002, 8:101-105.
• [12]Bauer J, Rauschka H, Lassmann H: Inflammation in the nervous system: the human perspective. Glia 2001, 36:235-243.
• [13]Schroeter M, Jander S: T-cell cytokines in injury-induced neural damage and repair. Neuromolecular Med 2005, 7:183-195.
• [14]Gaspar JM, Martins A, Cruz R, Rodrigues CM, Ambrosio AF, Santiago AR: Tauroursodeoxycholic acid protects retinal neural cells from cell death induced by prolonged exposure to elevated glucose. Neuroscience 2013, 253:380-388.
• [15]Rodrigues CM, Spellman SR, Sola S, Grande AW, Linehan-Stieers C, Low WC, Steer CJ: Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab 2002, 22:463-471.
• [16]Colak A, Kelten B, Sagmanligil A, Akdemir O, Karaoglan A, Sahan E, Celik O, Barut S: Tauroursodeoxycholic acid and secondary damage after spinal cord injury in rats. J Clin Neurosci 2008, 15:665-671.
• [17]Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC: Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A 2002, 99:10671-10676.
• [18]Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ: Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A 2003, 100:6087-6092.
• [19]Joo SS, Won TJ, Lee DI: Potential role of ursodeoxycholic acid in suppression of nuclear factor kappa B in microglial cell line (BV-2). Arch Pharm Res 2004, 27:954-960.
• [20]Poupon RE, Poupon R, Balkau B, The UDCA-PBC Study Group: Ursodiol for the long-term treatment of primary biliary cirrhosis. N Eng J Med 1994, 330:1342-1347.
• [21]Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates. San Diego: Academic; 1997.
• [22]Mecha M, Mestre L, Hernangómez M, Borrell J, Guaza C: An easy and fast way to obtain a high number of glial cells from rat cerebral tissue: a beginners approach. Protocol Exchange 2011, 218. doi:10.1038/protex.2011.218
• [23]McCarthy KD, de Vellis J: Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 1980, 85:890-902.
• [24]Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite, and [15 N]nitrate in biological fluids. Anal Biochem 1982, 126:131-138.
• [25]Saura M, Zaragoza C, Diaz-Cazorla M, Hernandez-Perera O, Eng E, Lowenstein CJ, Perez-Sala D, Lamas S: Involvement of transcriptional mechanisms in the inhibition of NOS2 expression by dexamethasone in rat mesangial cells. Kidney Int 1998, 53:38-49.
• [26]Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F: Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999, 274:10689-10692.
• [27]Yin JX, Tu JL, Lin HJ, Shi FD, Liu RL, Zhao CB, Coons SW, Kuniyoshi S, Shi J: Centrally administered pertussis toxin inhibits microglia migration to the spinal cord and prevents dissemination of disease in an EAE mouse model. PLoS One 2010, 5:e12400.
• [28]Carrigan SO, Pink DB, Stadnyk AW: Neutrophil transepithelial migration in response to the chemoattractant fMLP but not C5a is phospholipase D-dependent and related to the use of CD11b/CD18. J Leukoc Biol 2007, 82:1575-1584.
• [29]Cabanski M, Steinmuller M, Marsh LM, Surdziel E, Seeger W, Lohmeyer J: PKR regulates TLR2/TLR4-dependent signaling in murine alveolar macrophages. Am J Respir Cell Mol Biol 2008, 38:26-31.
• [30]Bonnet MC, Weil R, Dam E, Hovanessian AG, Meurs EF: PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol Cell Biol 2000, 20:4532-4542.
• [31]Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D: Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 2004, 24:10161-10168.
• [32]Weiss N, Miller F, Cazaubon S, Couraud PO: The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 2009, 1788:842-857.