Nogo receptor expression in microglia/macrophages during experimental autoimmune encephalomyelitis progression

Amani A. Alrehaili, Jae Lee, Maha M. Bakhuraysah, Min Joung Kim, Pei Mun Aui, Kylie A. Magee, Steven Petratos

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Myelin-associated inhibitory factors within the central nervous system (CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1 (NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis (MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis (EAE) was induced in ngr1 +/+ and ngr1 -/- female mice following injection with the myelin oligodendrocyte glycoprotein (MOG 35-55 ) peptide. A fate-map analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively (increasing locomotor disability) from both genotypes, using the CD11b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1 +/+ and ngr1 -/- mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1 +/+ and ngr1 -/- mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1 +/+ and ngr1 -/- mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of NgR on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1 -/- mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1 -/- mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1 -/- mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.

Original languageEnglish
Pages (from-to)896-907
Number of pages12
JournalNeural Regeneration Research
Issue number5
Publication statusPublished - 1 May 2018


  • experimental autoimmune encephalomyelitis
  • microglia
  • myelin-associated inhibitory factors (MAIFs)
  • neural regeneration
  • Nogo A
  • nogo receptor

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