TY - JOUR
T1 - Specialized differentially pro-resolving altered in peripheral lipid mediators blood of patients with multiple sclerosis and attenuate monocyte and blood-brain barrier dysfunction
AU - Kooij, Gijs
AU - Derada Troletti, Claudio
AU - Leuti, Alessandro
AU - Norris, Paul C
AU - Riley, Ian
AU - Albanese, Maria
AU - Ruggieri, Serena
AU - Libreros, Stephania
AU - van der Pol, Susanne M A
AU - van Het Hof, Bert
AU - Schell, Yoëlle
AU - Guerrera, Gisella
AU - Buttari, Fabio
AU - Mercuri, Nicola Biagio
AU - Centonze, Diego
AU - Gasperini, Claudio
AU - Battistini, Luca
AU - de Vries, Helga E
AU - Serhan, Charles N
AU - Chiurchiù, Valerio
N1 - Copyright © 2019, Ferrata Storti Foundation.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Chronic inflammation is a key pathological hallmark of multiple sclerosis and suggests that resolution of inflammation, orchestrated by specialized pro-resolving lipid mediators, is impaired. Here, through targeted-metabololipidomics in peripheral blood of patients with multiple sclerosis, we revealed that each disease form was associated with distinct lipid mediator profiles that significantly correlated with disease severity. In particular, relapsing and progressive multiple sclerosis patients were associated with high eicosanoids levels, whereas the majority of pro-resolving lipid mediators were significantly reduced or below limits of detection and correlated with disease progression. Furthermore, we found impaired expression of several pro-resolving lipid mediators biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients. Mechanistically, differentially expressed mediators like LXA4, LXB4, RvD1 and PD1 reduced multiple sclerosis-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 multiple sclerosis, suggesting pro-resolving lipid mediators as novel diagnostic biomarkers and potentially safe therapeutics.
AB - Chronic inflammation is a key pathological hallmark of multiple sclerosis and suggests that resolution of inflammation, orchestrated by specialized pro-resolving lipid mediators, is impaired. Here, through targeted-metabololipidomics in peripheral blood of patients with multiple sclerosis, we revealed that each disease form was associated with distinct lipid mediator profiles that significantly correlated with disease severity. In particular, relapsing and progressive multiple sclerosis patients were associated with high eicosanoids levels, whereas the majority of pro-resolving lipid mediators were significantly reduced or below limits of detection and correlated with disease progression. Furthermore, we found impaired expression of several pro-resolving lipid mediators biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients. Mechanistically, differentially expressed mediators like LXA4, LXB4, RvD1 and PD1 reduced multiple sclerosis-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 multiple sclerosis, suggesting pro-resolving lipid mediators as novel diagnostic biomarkers and potentially safe therapeutics.
UR - http://www.scopus.com/inward/record.url?scp=85089125447&partnerID=8YFLogxK
U2 - https://doi.org/10.3324/haematol.2019.219519
DO - https://doi.org/10.3324/haematol.2019.219519
M3 - Article
C2 - 31780628
SN - 0390-6078
VL - 105
SP - 2056
EP - 2070
JO - Haematologica
JF - Haematologica
IS - 8
ER -