title: The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy.
abstract: BACKGROUND
  Cervical compressive myelopathy, e.g. due to spondylosis or ossification of the posterior longitudinal ligament is a common cause of spinal cord dysfunction. Although human pathological studies have reported neuronal loss and demyelination in the chronically compressed spinal cord, little is known about the mechanisms involved. In particular, the neuroinflammatory processes that are thought to underlie the condition are poorly understood. The present study assessed the localized prevalence of activated M1 and M2 microglia/macrophages in twy/twy mice that develop spontaneous cervical spinal cord compression, as a model of human disease.
  
  
  METHODS
  Inflammatory cells and cytokines were assessed in compressed lesions of the spinal cords in 12-, 18- and 24-weeks old twy/twy mice by immunohistochemical, immunoblot and flow cytometric analysis. Computed tomography and standard histology confirmed a progressive spinal cord compression through the spontaneously development of an impinging calcified mass.
  
  
  RESULTS
  The prevalence of CD11b-positive cells, in the compressed spinal cord increased over time with a concurrent decrease in neurons. The CD11b-positive cell population was initially formed of arginase-1- and CD206-positive M2 microglia/macrophages, which later shifted towards iNOS- and CD16/32-positive M1 microglia/macrophages. There was a transient increase in levels of T helper 2 (Th2) cytokines at 18 weeks, whereas levels of Th1 cytokines as well as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and macrophage antigen (Mac)-2 progressively increased.
  
  
  CONCLUSIONS
  Spinal cord compression was associated with a temporal M2 microglia/macrophage response, which may act as a possible repair or neuroprotective mechanism. However, the persistence of the neural insult also associated with persistent expression of Th1 cytokines and increased prevalence of activated M1 microglia/macrophages, which may lead to neuronal loss and demyelination despite the presence of neurotrophic factors. This understanding of the aetiopathology of chronic spinal cord compression is of importance in the development of new treatment targets in human disease.
authors.affiliation: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hirai
authors.forename: Kenzo
authors.initials: K
authors.lastname: Uchida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Alexander Rodriguez
authors.initials: AR
authors.lastname: Guerrero
authors.forename: Naoto
authors.initials: N
authors.lastname: Takeura
authors.forename: Shuji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugita
authors.forename: Ai
authors.initials: A
authors.lastname: Yoshida
authors.forename: William E B
authors.initials: WE
authors.lastname: Johnson
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Baba
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D015576:Hyperostosis / Q000150:complications* / Q000175:diagnosis; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D010641:Phenotype; D015995:Prevalence; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013117:Spinal Cord Compression / Q000175:diagnosis / Q000209:etiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells; D014057:Tomography, X-Ray Computed
chemical_list: D016207:Cytokines; D009414:Nerve Growth Factors