title: Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages.
abstract: Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2+ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair.
  
  
  CONCLUSIONS
  There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research. In this report, using in vitro and in vivo models of relevance to traumatic spinal cord injury (SCI), new data indicate that stochastic activation of toll-like and c-type lectin receptors on macrophages causes neuroprotection or neurotoxicity, respectively. Although this manuscript focuses on SCI, these two innate immune receptor subtypes are also involved in developmental processes and become activated in macrophages that respond to various neurological diseases.
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, and gensel.1@uky.edu Phillip.Popovich@osumc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Gensel
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Beckwith
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, and.
authors.forename: Kaitlyn J
authors.initials: KJ
authors.lastname: Braun
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210.
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210.
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210 gensel.1@uky.edu Phillip.Popovich@osumc.edu.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D039481:CD11b Antigen; D017077:Culture Media, Conditioned; D037181:Lectins, C-Type; D055666:Lipopeptides; D009419:Nerve Tissue Proteins; D051195:Toll-Like Receptor 2; D000099181:Dectin-1; C560312:Pam2CSK4 lipopeptide; C493486:Tlr2 protein, mouse
keywords: TLR2; dieback; microglia; neuroinflammation; regeneration; zymosan