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Maresin 1 Promotes Inflammatory Resolution, Neuroprotection and Functional Neurological Recovery After Spinal Cord Injury

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Maresin 1 Promotes Inflammatory Resolution, Neuroprotection and Functional Neurological Recovery After Spinal Cord Injury This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Maresin 1 promotes inflammatory resolution, neuroprotection and functional neurological recovery after spinal cord injury Isaac Francos Quijorna1, Eva Santos-Nogueira1, Karsten Gronert2, Aaron B. Sullivan2, Marcel A Kopp3, Benedikt Brommer3,4, Samuel David5, Jan M. Schwab3,6,7 and Ruben Lopez Vales1 1Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia Spain 2Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598, USA 3Spinal Cord Alliance Berlin (SCAB) and Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany 4F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 5Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Canada 6Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA 7Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA. DOI: 10.1523/JNEUROSCI.1395-17.2017 Received: 22 May 2017 Revised: 27 September 2017 Accepted: 1 October 2017 Published: 3 November 2017 Author contributions: I.F.Q., J.S., and R.L.-V. designed research; I.F.Q., E.S.-N., M.K., B.B., J.S., and R.L.-V. performed research; I.F.Q., K.G., A.S., M.K., B.B., and R.L.-V. analyzed data; S.D. and J.S. contributed unpublished reagents/analytic tools; S.D., J.S., and R.L.-V. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work has been supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2010-17851; SAF2013-48431-R), International Foundation for Research in Paraplegia and by funds from the Fondo de Investigación Sanitaria of Spain (TERCEL and CIBERNED) to R.L-V. JMS received funding from the Wings for Life Spinal Cord Research Foundation, the Era-Net-NEURON Program of the European Union (SILENCE #01EW170A), NIDILRR (#90SI5020), and the W.E. Hunt & C.M. Curtis Endowment. KG received funding from the National Institutes of Health (EY026082). The authors IFQ, SD, JMS and RLV are inventors on a patent application filled by Universitat Autònoma de Barcelona (Maresins for use in the treatment of CNS injuries, PCT/IB2017/054398) Correspondence: Ruben Lopez Vales, PhD, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain., Email: [email protected] or Jan M. Schwab, MD, PhD, The Neurological Institute, The Ohio State University - Wexner Medical Center, 395 W. 12th Ave, 7th Floor, Columbus, OH 43210, USA., Email: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.1395-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2017 the authors 1 2 Maresin 1 promotes inflammatory resolution, neuroprotection and functional 3 neurological recovery after spinal cord injury 4 Isaac Francos Quijorna1, Eva Santos-Nogueira1 , Karsten Gronert2, Aaron B. Sullivan2 , 5 Marcel A Kopp3, Benedikt Brommer3,4, Samuel David5, Jan M. Schwab3,6,7, Ruben 6 Lopez Vales1. 7 1Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de 8 Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat 9 Autònoma de Barcelona, 08193 Bellaterra, Catalonia Spain, 10 2Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598, 11 USA, 12 3Spinal Cord Alliance Berlin (SCAB) and Department of Neurology and Experimental Neurology, 13 Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory 14 (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany, 15 4F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard 16 Medical School, 300 Longwood Avenue, Boston, MA 02115, USA, 17 5Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, 18 Montreal, Canada, 19 6Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State 20 University, Wexner Medical Centre, Columbus, OH 43210, USA, 21 7Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical 22 Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical 23 Centre, Columbus, OH 43210, USA. 24 25 Running title: Maresin 1 in spinal cord injury 26 27 Correspondence: 28 Ruben Lopez Vales, PhD 29 Departament de Biologia Cel·lular, Fisiologia i Immunologia, 30 Institut de Neurociències, Centro de Investigación Biomédica en Red sobre 31 Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 32 Bellaterra, Catalonia, Spain. 33 Email: [email protected] 34 35 or 36 Jan M. Schwab, MD, PhD 37 The Neurological Institute, The Ohio State University - Wexner Medical Center 38 395 W. 12th Ave, 7th Floor, Columbus, OH 43210, USA. 39 Email: [email protected] 40 41 Number of pages 28; Words Abstract 249; Words Introduction: 636; Words 42 Discussion 1438: 43 Number of Figures: 8; Number of Tables: 1 1 44 45 ACKNOWLEDGMENTS 46 This work has been supported by grants from the Spanish Ministry of Economy and 47 Competitiveness (SAF2010-17851; SAF2013-48431-R), International Foundation for 48 Research in Paraplegia and by funds from the Fondo de Investigación Sanitaria of Spain 49 (TERCEL and CIBERNED) to R.L-V. JMS received funding from the Wings for Life 50 Spinal Cord Research Foundation, the Era-Net-NEURON Program of the European 51 Union (SILENCE #01EW170A) , NIDILRR (#90SI5020), and the W.E. Hunt & C.M. 52 Curtis Endowment. KG received funding from the National Institutes of Health 53 (EY026082). The authors IFQ, SD, JMS and RLV are inventors on a patent application 54 filled by Universitat Autònoma de Barcelona (Maresins for use in the treatment of CNS 55 injuries, PCT/IB2017/054398) 56 57 2 58 ABSTRACT 59 Resolution of inflammation is defective after spinal cord injury (SCI), which impairs 60 tissue integrity and remodelling, and leads to functional deficits. Effective treatments 61 for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized 62 pro-resolving mediators (SPM) hosting potent anti-inflammatory and pro-resolving 63 properties with potent tissue regenerative actions. Here, we provide evidence that the 64 inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of 65 inflammation and leads to deleterious consequences on neurological outcome in adult 66 female mice. We report that after spinal cord contusion injury in adult female mice, the 67 biosynthesis of SPM is not induced in the lesion site up to 2 weeks post-injury. 68 Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory 69 resolution after SCI, as revealed by accelerated clearance of neutrophils and the 70 reduction in macrophage accumulation at the lesion site. In the search of mechanisms 71 underlying the pro-resolving actions of MaR1 in SCI, we found that this SPM facilitated 72 several hallmarks of resolution of inflammation, including reduction of pro- 73 inflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, CSF3), silencing of 74 major inflammatory intracellular signalling cascades (STAT1, STAT3, STAT5, p38, 75 ERK1/2), redirection of macrophage activation towards a pro-repair phenotype, and 76 increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, 77 MaR1 administration significantly improved locomotor recovery and mitigated 78 secondary injury progression in a clinical relevant model of SCI. These findings suggest 79 that pro-resolution namely immunoresolvent therapies would be a novel approach to 80 improve neurological recovery after acute spinal cord injury. 81 82 Keywords: Inflammation, lipid mediators, Maresin 1, Resolution, Spinal Cord Injury 83 84 SIGNIFICANT STATEMENT 85 Inflammation is a protective response to injury or infection. In order to result in tissue 86 homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution 87 leads to detrimental effects, including propagated tissue damage and impaired would 88 healing, as it occurs after spinal cord injury. We report that inflammation after spinal 89 cord injury is dysregulated, in part, due to inappropriate synthesis of pro-resolving lipid 90 mediators. We demonstrate that the administration of the resolution agonist, referred to 3 91 as maresin 1, after spinal cord injury
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