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      This image shows a macrophage extending its 'arms' to engulf two particles.
      The researchs looked at more than 50 animals with spinal cord injury to try to identify which macrophage receptors promoted neuronal repair and which directed the destructive process. This image is for illustrative purposes only. Image credit: Obli.

      Repair or Destroy? Identifying the Receptors Modulating Macrophage Response to Spinal Cord Injury

      FeaturedNeurology
      ·July 10, 2015

      Macrophages are cellular sentinels in the body, assigned to identify “attacks” from viruses, bacteria, or fungi and sound the alarm when they are present. However, these cells are a “double edged sword” in spinal cord injury, providing both neural repair-promoting properties and pathological functions that destroy neuronal tissue.

      “We know from previous research that macrophages are versatile, and signals at the injury site can stimulate repair or destruction–or confusingly, both,” said John Gensel Ph.D., Assistant Professor of Physiology in the Spinal Cord and Brain Injury Research Center at the University of Kentucky. “But the mechanisms through which these signals stimulate the good and/or bad functions in macrophages are not known. So the next big question to answer in the efforts to understand and treat SCI was, ‘Why?'”

      Gensel teamed up with Phillip Popovich, Ph.D, Professor in the Department of Neuroscience and Director of the Center for Brain and Spinal Cord Repair (CBSCR) at The Ohio State University to explore the mechanisms governing the positive and negative processes that occur in macrophages following spinal cord injury.

      “On the cellular level, the body’s response to spinal cord injury is similar to the immune response to attacks by bacteria or viruses,” Gensel said. “The functions that macrophages adopt in response to these stimuli were the focus of our study.”

      Gensel and Popovich looked at more than 50 animals with spinal cord injury to try to identify which macrophage receptors promoted neuronal repair and which directed the destructive process.

      “We found that activating bacterial receptors boosted the macrophage response and limited damage to the spinal cord following injury, while activating fungal receptors actually contributed to pathology,” Gensel said.

      This image shows a macrophage extending its 'arms' to engulf two particles.
      The researchers looked at more than 50 animals with spinal cord injury to try to identify which macrophage receptors promoted neuronal repair and which directed the destructive process. This image is for illustrative purposes only. Image credit: Obli.

      While this study oversimplifies the complex process by which macrophages promote repair and destruction of neuronal tissues, it nonetheless sheds light on opportunities to modulate macrophage responses after spinal cord injury, potentially reducing – or even reversing – damage and the resulting side-effects.

      “The implications are exciting: we now can look for treatments targeted to the receptors that jump-start the macrophage’s restorative effects without activating the receptors that modulate the destructive processes in that same cell.”

      About this neuroscience research

      Source: Laura Dawahare – University of Kentucky
      Image Credit: Image is credited to Obli and is licensed CC BY-SA 2.0
      Original Research: Abstract for “Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages” by John C. Gensel, Yan Wang, Zhen Guan, Kyle A. Beckwith, Kaitlyn J. Braun, Ping Wei, Dana M. McTigue, and Phillip G. Popovich in Journal of Neuroscience. Published online July 8 2015 doi:10.1523/JNEUROSCI.0337-15.2015


      Abstract

      Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages

      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.

      SIGNIFICANCE STATEMENT 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.

      “Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages” by John C. Gensel, Yan Wang, Zhen Guan, Kyle A. Beckwith, Kaitlyn J. Braun, Ping Wei, Dana M. McTigue, and Phillip G. Popovich in Journal of Neuroscience. Published online July 8 2015 doi:10.1523/JNEUROSCI.0337-15.2015

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      Tags
      C-Type Lectin Receptorcentral nervous systemDectin-1macrophagesneurogenesisNeurologyneuronal repairNeuroscienceNG2+ cellsspinal cord injuryTLR2toll-like receptors
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