Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs
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.
KeywordsSpecialized pro-resolving mediators Inflammation resolution Neuroinflammation Remote brain damage Epigenetics
Glial fibrillary acidic protein
Specialized pro-resolving mediators
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.
- 1.Tator CH (1995) Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5(4):407–413. https://doi.org/10.1111/j.1750-3639.1995.tb00619.x CrossRefPubMedGoogle Scholar
- 4.Viscomi MT, Florenzano F, Latini L, Amantea D, Bernardi G, Molinari M (2008) Methylprednisolone treatment delays remote cell death after focal brain lesion. Neuroscience 154(4):1267–1282. https://doi.org/10.1016/j.neuroscience.2008.04.024 CrossRefPubMedGoogle Scholar
- 7.Cavallucci V, Bisicchia E, Cencioni MT, Ferri A, Latini L, Nobili A, Biamonte F, Nazio F et al (2014) Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons. Cell Death Dis 5(11):e1545. https://doi.org/10.1038/cddis.2014.511 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Bisicchia E, Chiurchiù V, Viscomi MT, Latini L, Fezza F, Battistini L, Maccarrone M, Molinari M (2013) Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor alpha: when one is better than two. Cell Mol Life Sci 70(12):2191–2204. https://doi.org/10.1007/s00018-012-1253-5 CrossRefPubMedGoogle Scholar
- 18.Kongsui R, Beynon SB, Johnson SJ, Walker FR (2014) Quantitative assessment of microglial morphology and density reveals remarkable consistency in the distribution and morphology of cells within the healthy prefrontal cortex of the rat. J Neuroinflammation 11(1):182. https://doi.org/10.1186/s12974-014-0182-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Rius B, Titos E, Morán-Salvador E, López-Vicario C, García-Alonso V, González-Périz A, Arroyo V, Clària J (2014) Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis. FASEB J 28(2):836–848. https://doi.org/10.1096/fj.13-235614 CrossRefPubMedGoogle Scholar
- 27.Hall JC, Priestley JV, Perry VH, Michael-Titus AT (2012) Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early inflammatory response following compression spinal cord injury in the rat. J Neurochem 121(5):738–750. https://doi.org/10.1111/j.1471-4159.2012.07726.x CrossRefPubMedGoogle Scholar
- 29.Kong Y, Ruan L, Qian L, Liu X, Le Y (2010) Norepinephrine promotes microglia to uptake and degrade amyloid beta peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme. J Neurosci 30(35):11848–11857. https://doi.org/10.1523/JNEUROSCI.2985-10.2010 CrossRefPubMedGoogle Scholar
- 35.Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32(1):367–402. https://doi.org/10.1146/annurev-immunol-032713-120240 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Beynon SB, Walker FR (2012) Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225:162–171. https://doi.org/10.1016/j.neuroscience.2012.07.029 CrossRefPubMedGoogle Scholar
- 45.Codagnone M, Cianci E, Lamolinara A, Mari VC, Nespoli A, Isopi E, Mattoscio D, Arita M, Bragonzi A, Iezzi M, Romano M, Recchiuti A (2017) Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection. Mucosal ImmunolGoogle Scholar
- 47.Caiello I, Minnone G, Holzinger D, Vogl T, Prencipe G, Manzo A, De Benedetti F, Strippoli R (2014) IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases. PLoS One 9(10):e107886. https://doi.org/10.1371/journal.pone.0107886 CrossRefPubMedPubMedCentralGoogle Scholar