Specialized pro-resolving lipid mediators are differentially altered in peripheral blood of patients with multiple sclerosis and attenuate monocyte and blood-brain barrier dysfunction
Gijs Kooij*,
Claudio Derada Troletti*,
Alessandro Leuti,
Paul C. Norris,
Ian Riley,
Maria Albanese,
Serena Ruggieri,
Stephania Libreros,
Susanne M.A. van der Pol,
Bert van het Hof,
Yoëlle Schell,
Gisella Guerrera,
Fabio Buttari,
Nicola Biagio Mercuri,
Diego Centonze,
Claudio Gasperini,
Luca Battistini,
Helga E. de Vries,
Charles N. Serhan#,
Valerio Chiurchiù#
Affiliations
Gijs Kooij*
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands;Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Claudio Derada Troletti*
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
Alessandro Leuti
Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy;European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
Paul C. Norris
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Ian Riley
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Maria Albanese
Neurology Unit, Department of Neurosciences, University of Rome Tor Vergata, Rome, Italy
Serena Ruggieri
Neurology Unit, San Camillo Forlanini Hospital, Rome, Italy
Stephania Libreros
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Susanne M.A. van der Pol
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
Bert van het Hof
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
Yoëlle Schell
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
Gisella Guerrera
European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
Fabio Buttari
Unit of Neurology and Unit of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, IS, Italy
Nicola Biagio Mercuri
European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy;Neurology Unit, Department of Neurosciences, University of Rome Tor Vergata, Rome, Italy
Diego Centonze
Neurology Unit, Department of Neurosciences, University of Rome Tor Vergata, Rome, Italy;Unit of Neurology and Unit of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, IS, Italy
Claudio Gasperini
Neurology Unit, San Camillo Forlanini Hospital, Rome, Italy
Luca Battistini
European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
Helga E. de Vries
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
Charles N. Serhan#
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Valerio Chiurchiù#
Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy;European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
Chronic inflammation is a key pathological hallmark of multiple sclerosis (MS) and suggests that resolution of inflammation, orchestrated by specialized pro-resolving lipid mediators (LM), is impaired. Here, through targeted-metabololipidomics in peripheral blood of patients with MS, we revealed that each disease form was associated with distinct LM profiles that significantly correlated with disease severity. In particular, relapsing and progressive MS patients were associated with high eicosanoids levels, whereas the majority of pro-resolving LM were significantly reduced or below limits of detection and correlated with disease progression. Furthermore, we found impaired expression of several pro-resolving LM biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients. Mechanistically, differentially expressed mediators like LXA4, LXB4, RvD1 and PD1 reduced MS-derived monocyte activation and cytokine production, and inhibited inflammation-induced blood-brain barrier dysfunction and monocyte transendothelial migration. Altogether, these findings reveal peripheral defects in the resolution pathway in MS, suggesting pro-resolving LM as novel diagnostic biomarkers and potentially safe therapeutics.
