title: miR-155 Deletion in Mice Overcomes Neuron-Intrinsic and Neuron-Extrinsic Barriers to Spinal Cord Repair.
abstract: Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers including inflammation. microRNA (miR)-155-5p is a small, noncoding RNA that negatively regulates mRNA translation. In macrophages, miR-155-5p is induced by inflammatory stimuli and elicits a response that could be toxic after SCI. miR-155 may also independently alter expression of genes that regulate axon growth in neurons. Here, we hypothesized that miR-155 deletion would simultaneously improve axon growth and reduce neuroinflammation after SCI by acting on both neurons and macrophages. New data show that miR-155 deletion attenuates inflammatory signaling in macrophages, reduces macrophage-mediated neuron toxicity, and increases macrophage-elicited axon growth by ∼40% relative to control conditions. In addition, miR-155 deletion increases spontaneous axon growth from neurons; adult miR-155 KO dorsal root ganglion (DRG) neurons extend 44% longer neurites than WT neurons. In vivo, miR-155 deletion augments conditioning lesion-induced intraneuronal expression of SPRR1A, a regeneration-associated gene; ∼50% more injured KO DRG neurons expressed SPRR1A versus WT neurons. After dorsal column SCI, miR-155 KO mouse spinal cord has reduced neuroinflammation and increased peripheral conditioning-lesion-enhanced axon regeneration beyond the epicenter. Finally, in a model of spinal contusion injury, miR-155 deletion improves locomotor function at postinjury times corresponding with the arrival and maximal appearance of activated intraspinal macrophages. In miR-155 KO mice, improved locomotor function is associated with smaller contusion lesions and decreased accumulation of inflammatory macrophages. Collectively, these data indicate that miR-155 is a novel therapeutic target capable of simultaneously overcoming neuron-intrinsic and neuron-extrinsic barriers to repair after SCI.
  
  
  
  Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers, including inflammation. Here, new data show that deleting microRNA-155 (miR-155) affects both mechanisms and improves repair and functional recovery after SCI. Macrophages lacking miR-155 have altered inflammatory capacity, which enhances neuron survival and axon growth of cocultured neurons. In addition, independent of macrophages, adult miR-155 KO neurons show enhanced spontaneous axon growth. Using either spinal cord dorsal column crush or contusion injury models, miR-155 deletion improves indices of repair and recovery. Therefore, miR-155 has a dual role in regulating spinal cord repair and may be a novel therapeutic target for SCI and other CNS pathologies.
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center, andrew.gaudet@colorado.edu phillip.popovich@osumc.edu.
authors: Andrew D
authors: 0000-0001-8828-1553
authors: AD
authors: Gaudet
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: Shweta
authors: 0000-0002-4296-302X
authors: S
authors: Mandrekar-Colucci
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: Jodie C E
authors: 0000-0002-4820-6070
authors: JC
authors: Hall
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: David R
authors: 0000-0002-1982-2958
authors: DR
authors: Sweet
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: Philipp J
authors: 0000-0002-8704-8714
authors: PJ
authors: Schmitt
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: Xinyang
authors: 0000-0002-8958-2005
authors: X
authors: Xu
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center.
authors: Zhen
authors: Z
authors: Guan
authors: Center for Biostatistics, and.
authors: Xiaokui
authors: X
authors: Mo
authors: Department of Neuroscience, Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, Ohio 43210.
authors: Mireia
authors: 0000-0002-0600-4593
authors: M
authors: Guerau-de-Arellano
authors: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center, andrew.gaudet@colorado.edu phillip.popovich@osumc.edu.
authors: Phillip G
authors: 0000-0003-1329-7395
authors: PG
authors: Popovich
mesh_terms: D000818:Animals; D001369:Axons; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D016501:Neurites; D009474:Neurons / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology*; D058630:Spinal Cord Regeneration / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D035683:MicroRNAs; D008840:Microfilament Proteins; C532623:Mirn155 microRNA, mouse; D011956:Receptors, Cell Surface; D049452:Green Fluorescent Proteins
keywords: axon regeneration; microRNA; neuroinflammation; neuroprotection; spinal cord injury