Urolithins and their phase II conjugates cross the blood–brain barrier and exert a stimulus-dependent anti-inflammatory effect on microglial cells by inhibiting NF-κB nuclear translocation
Beatriz Garay-Mayol, Juan Antonio Giménez‐Bastida, Diego José López-Cánovas, Sabrina Poveda-Lora, Silvia Navarro‐Orcajada, María Alexandra Brito, Cláudia Nunes dos Santos, Juan Carlos Espı́n, María Ángeles Ávila‐Gálvez, Antonio González‐Sarrías
Abstract
model of the blood-brain barrier (BBB), and assessed their anti-(neuro)inflammatory effects on the BBB endothelium and human microglial cells (HMC3) under different inflammatory stimuli. UPLC-qTOF-MS analyses revealed that all Uros and their conjugates crossed the BBB, with Uro-B and its sulphate showing the highest transport efficiency. Moreover, Uros preserved BBB integrity against TNFα-induced damage. In HMC3 cells, all Uros significantly reduced IL-6 secretion, whereas only the free forms decreased IL-8 levels under LPS stimulation. However, no effects were observed in TNFα-stimulated cells, indicating a stimulus-dependent response. Additionally, all Uros prevented NF-κB nuclear translocation in LPS-treated cells, and Uro-A specifically interfered with the canonical MyD88-dependent arm of TLR4 signalling, without broadly inhibiting receptor expression or affecting the TRIF-dependent branch. These findings suggest that consuming ETs and EA-rich foods as precursors of Uros could exert anti-neuroinflammatory activity, potentially preventing or delaying the development of neurodegenerative diseases.