title: Increased circulating leukocyte numbers and altered macrophage phenotype correlate with the altered immune response to brain injury in metallothionein (MT)-I/II null mutant mice.
abstract: BACKGROUND
  Metallothionein-I and -II (MT-I/II) is produced by reactive astrocytes in the injured brain and has been shown to have neuroprotective effects. The neuroprotective effects of MT-I/II can be replicated in vitro which suggests that MT-I/II may act directly on injured neurons. However, MT-I/II is also known to modulate the immune system and inflammatory processes mediated by the immune system can exacerbate brain injury. The present study tests the hypothesis that MT-I/II may have an indirect neuroprotective action via modulation of the immune system.
  
  
  METHODS
  Wild type and MT-I/II(-/-) mice were administered cryolesion brain injury and the progression of brain injury was compared by immunohistochemistry and quantitative reverse-transcriptase PCR. The levels of circulating leukocytes in the two strains were compared by flow cytometry and plasma cytokines were assayed by immunoassay.
  
  
  RESULTS
  Comparison of MT-I/II(-/-) mice with wild type controls following cryolesion brain injury revealed that the MT-I/II(-/-) mice only showed increased rates of neuron death after 7 days post-injury (DPI). This coincided with increases in numbers of T cells in the injury site, increased IL-2 levels in plasma and increased circulating leukocyte numbers in MT-I/II(-/-) mice which were only significant at 7 DPI relative to wild type mice. Examination of mRNA for the marker of alternatively activated macrophages, Ym1, revealed a decreased expression level in circulating monocytes and brain of MT-I/II(-/-) mice that was independent of brain injury.
  
  
  CONCLUSIONS
  These results contribute to the evidence that MT-I/II(-/-) mice have altered immune system function and provide a new hypothesis that this alteration is partly responsible for the differences observed in MT-I/II(-/-) mice after brain injury relative to wild type mice.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia. Michael.pankhurst@anatomy.otago.ac.nz
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pankhurst
authors.forename: William
authors.initials: W
authors.lastname: Bennett
authors.forename: Matthew T K
authors.initials: MT
authors.lastname: Kirkcaldie
authors.forename: Adrian K
authors.initials: AK
authors.lastname: West
authors.forename: Roger S
authors.initials: RS
authors.lastname: Chung
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001930:Brain Injuries / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D018696:Neuroprotective Agents; D008668:Metallothionein