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

Michael W. Pankhurst*, William Bennett, Matthew T K Kirkcaldie, Adrian K. West, Roger S. Chung

*Corresponding author for this work

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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.

Original languageEnglish
Article number172
Pages (from-to)1-11
Number of pages11
JournalJournal of Neuroinflammation
Volume8
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

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