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Resolving mediators are altered in multiple sclerosis
mation, but also that specific SPM (LXA4, LXB4, RvD1 and PD1) can prevent inflammation-induced BBB dysfunction, and reduce monocyte transmigration, as well as expres- sion of ICAM-1 adhesion molecule and production of CCL2 chemokine. Our results confirm and extend previ- ous findings in which SPM have been shown to positively regulate endothelial barrier functions through different mechanisms of action. Indeed, it has been shown that LXA4 and RvD1 were able to protect LPS-induced barrier integrity and function via suppression of reactive oxygen species (ROS) production,50 inhibition of the NF-kB path- way51 or induction of the antioxidant protein Nrf2.52 Furthermore, SPM like (AT)-LXA4, RvD1, RvD2, and MaR1 were reported to reduce monocyte/macrophage infiltration and chemotaxis both in vitro and in vivo,53,54 with RvD1 also being able to induce a switch to the anti- inflammatory M2 phenotype on monocyte-derived brain macrophages in the murine model of MS.40 Although sev- eral studies report the anti-inflammatory role of different SPM (LXA4 in particular) on vascular endothelial cells or monocytes/macrophages, in terms of reduction of ICAM- 1 expression55,56 and CCL2 production,57 we are the first to reveal potent SPM effects on the BBB, therefore providing novel tools to counteract inflammation-induced BBB dys- function.
In conclusion, we provide here a comprehensive profil- ing of the LM signature in plasma from MS patients with different clinical forms of the disease compared to healthy controls. Importantly, our data indicate that key SPM are
lacking at different disease stages, which not only indicates a failed resolution response in these individuals, but may also provide an explanation as to why the disease progress- es. It may also hint at novel therapeutic strategies aimed at boosting their endogenous production or at activating their target receptors. At a functional level, we here show that LXA4, LXB4, RvD1 and PD1 significantly reduce the inflam- matory profile of MS-patient-derived monocytes and potently inhibit inflammation-induced BBB dysfunction and monocyte-BBB traversal, which are key pathological hallmarks of MS lesion development. Although further investigations are needed to verify whether SPM impair- ment is also associated to demyelination and behavior/motor functions in MS patients, this study high- lights the potential to use SPM as novel blood biomarkers for MS diagnosis and provides novel tools to ultimately limit MS pathogenesis at several clinical disease stages.
Funding
This study was supported by the Italian Foundation of Multiple Sclerosis (FISM grant 2017/R/08 to VC) and Ministry of Health, Progetto Giovani Ricercatori (GR-2016-02362380 to VC), Nauta Fonds and VUmc MS Center Amsterdam (to GK), Dutch MS Research Foundation (14-878MS to GK), by the European Union's Seventh Framework Program FP7 under Grant agreement 607962 (nEUROinflammation) (to CDT) and studies in the CNS laboratories were supported by NIH/NIGMS (Grant P01GM095467). GK was supported by an IBRO Research Fellowship.
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