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Molecular Neurobiology

, Volume 55, Issue 8, pp 6894–6905 | Cite as

Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs

  • Elisa Bisicchia
  • Valeria Sasso
  • Giuseppina Catanzaro
  • Alessandro Leuti
  • Zein Mersini Besharat
  • Martina Chiacchiarini
  • Marco Molinari
  • Elisabetta Ferretti
  • Maria Teresa Viscomi
  • Valerio Chiurchiù
Article

Abstract

Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b- and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage.

Keywords

Specialized pro-resolving mediators Inflammation resolution Neuroinflammation Remote brain damage Epigenetics 

Abbreviations

GFAP

Glial fibrillary acidic protein

HCb

Hemicerebellectomy

Rv

Resolvin

RvD1

Resolvin D1

SPM

Specialized pro-resolving mediators

Notes

Funding information

This work was funded by Fondazione Italiana Sclerosi Multipla (FISM) (grant 2015/R/8 to V.C.) and by the Italian Ministry of Health (Progetto Giovani Ricercatori Project Code GR-2010.2310524 to M.T.V.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.IRCCS Santa Lucia FoundationRomeItaly
  2. 2.Department of Experimental MedicineSapienza University of RomeRomeItaly
  3. 3.Department of Molecular MedicineSapienza University of RomeRomeItaly
  4. 4.IRCCS NeuromedPozzilliItaly
  5. 5.Department of MedicineCampus Bio-Medico University of RomeRomeItaly

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