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

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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.

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Abbreviations

GFAP:

Glial fibrillary acidic protein

HCb:

Hemicerebellectomy

Rv:

Resolvin

RvD1:

Resolvin D1

SPM:

Specialized pro-resolving mediators

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Funding

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.).

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Authors and Affiliations

  1. IRCCS Santa Lucia Foundation, via del Fosso di Fiorano 64, 00143, Rome, Italy

    Elisa Bisicchia, Valeria Sasso, Alessandro Leuti, Marco Molinari, Maria Teresa Viscomi & Valerio Chiurchiù

  2. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Giuseppina Catanzaro, Zein Mersini Besharat & Elisabetta Ferretti

  3. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Martina Chiacchiarini

  4. IRCCS Neuromed, Pozzilli, Italy

    Elisabetta Ferretti

  5. Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy

    Valerio Chiurchiù

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  1. Elisa Bisicchia
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  2. Valeria Sasso
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  3. Giuseppina Catanzaro
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  4. Alessandro Leuti
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Correspondence to Maria Teresa Viscomi or Valerio Chiurchiù.

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Maria Teresa Viscomi and Valerio Chiurchiù equally senior authors

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Bisicchia, E., Sasso, V., Catanzaro, G. et al. Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs. Mol Neurobiol 55, 6894–6905 (2018). https://doi.org/10.1007/s12035-018-0889-z

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