title: TGFβ Contributes to the Anti-inflammatory Effects of Tauroursodeoxycholic Acid on an Animal Model of Acute Neuroinflammation.
abstract: The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in various animal models of neuropathologies. We have previously shown the anti-inflammatory properties of TUDCA in an animal model of acute neuroinflammation. Here, we present a new anti-inflammatory mechanism of TUDCA through the regulation of transforming growth factor β (TGFβ) pathway. The bacterial lipopolysaccharide (LPS) was injected intravenously (iv) on TGFβ reporter mice (Smad-binding element (SBE)/Tk-Luc) to study in their brains the real-time activation profile of the TGFβ pathway in a non-invasive way. The activation of the TGFβ pathway in the brain of SBE/Tk-Luc mice increased 24 h after LPS injection, compared to control animals. This activation peak increased further in mice treated with both LPS and TUDCA than in mice treated with LPS only. The enhanced TGFβ activation in mice treated with LPS and TUDCA correlated with both an increase in TGFβ3 transcript in mouse brain and an increase in TGFβ3 immunoreactivity in microglia/macrophages, endothelial cells, and neurons. Inhibition of the TGFβ receptor with SB431542 drug reverted the effect of TUDCA on microglia/macrophages activation and on TGFβ3 immunoreactivity. Under inflammatory conditions, treatment with TUDCA enhanced further the activation of TGFβ pathway in mouse brain and increased the expression of TGFβ3. Therefore, the induction of TGFβ3 by TUDCA might act as a positive feedback, increasing the initial activation of the TGFβ pathway by the inflammatory stimulus. Our findings provide proof-of-concept that TGFβ contributes to the anti-inflammatory effect of TUDCA under neuroinflammatory conditions.
authors.affiliation: Laboratorio de Plasticidad Neural. Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.|Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yanguas-Casás
authors.affiliation: Laboratorio de Plasticidad Neural. Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.|Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002, Madrid, Spain.
authors.forename: M Asunción
authors.initials: MA
authors.lastname: Barreda-Manso
authors.affiliation: Laboratorio de Neumología, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-CIBERES, Avenida Reyes Católicos 2, 28040, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pérez-Rial
authors.affiliation: Laboratorio de Plasticidad Neural. Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain.|Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.affiliation: Laboratorio de Plasticidad Neural. Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071, Toledo, Spain. lromeroramirez@sescam.jccm.es.
authors.forename: Lorenzo
authors.identifier: http://orcid.org/0000-0002-8974-6698
authors.initials: L
authors.lastname: Romero-Ramírez
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D007249:Inflammation / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
chemical_list: D000893:Anti-Inflammatory Agents; D016212:Transforming Growth Factor beta; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: Lipopolysaccharide; Neuroinflammation; SBE/Tk-Luc mice; TGFβ; TGFβ3; TUDCA