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Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2056-2070
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,1,2* Claudio Derada Troletti,1* Alessandro Leuti,3,4 Paul C. Norris,2
Ian Riley,2 Maria Albanese,5 Serena Ruggieri,6 Stephania Libreros,2
Susanne M.A. van der Pol,1 Bert van het Hof,1 Yoëlle Schell,1
Gisella Guerrera,4 Fabio Buttari,7 Nicola Biagio Mercuri,4,5 Diego Centonze,5,7
6 4 1 2# Claudio Gasperini, Luca Battistini, Helga E. de Vries, Charles N. Serhan,
3,4# Valerio Chiurchiù
1Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands; 2Center 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; 3Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; 4European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy; 5Neurology Unit, Department of Neurosciences, University of Rome Tor Vergata, Rome, Italy; 6Neurology Unit, San Camillo Forlanini Hospital, Rome, Italy and 7Unit of Neurology and Unit of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, IS, Italy
ABSTRACT
Chronic inflammation is a key pathological hallmark of multiple scle- rosis (MS) and suggests that resolution of inflammation, orchestrat- ed 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 signifi- cantly reduced or below limits of detection and correlated with disease pro- gression. Furthermore, we found impaired expression of several pro-resolv- ing 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 bar- rier 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.
Introduction
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) associated to uncontrolled/excessive neuro-inflammation and autoimmunity.1,2 The underlying immunopathogenesis of the disease has been extensively studied and is currently thought to involve an ini- tial alteration of peripheral and brain immune responses, as well as a disruption of the blood-brain barrier (BBB). Subsequently, this leads to a substantial infiltration of autoreactive lymphocytes and innate immune cells causing demyelination, axon- al loss, and ultimately neurodegeneration.3-6 Nevertheless, there is still an unmet need for new diagnostic and therapeutic options, especially for the progressive forms of MS for which almost no drugs are available (with the exception of the off- label rituximab and the recently approved ocrelizumab for the management of pri-
*GK and CDT contributed equally as first authors. #ECNS and VC contributed equally as co-senior authors.
Correspondence:
VALERIO CHIURCHIÙ
v.chiurchiu@hsantalucia.it
CHARLES N. SERHAN
cserhan@bwh.harvard.edu
Received: February 13, 2019. Accepted: November 21, 2019. Pre-published: November 28, 2019.
doi:10.3324/haematol.2019.219519
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