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Open Access Research

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 Pankhurst12*, William Bennett1, Matthew TK Kirkcaldie3, Adrian K West1 and Roger S Chung1

Author Affiliations

1 Menzies Research Institute Tasmania, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania, Australia

2 Department of Anatomy, University of Otago, 270 Great King St, Dunedin, New Zealand

3 School of Medicine, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania, Australia

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Journal of Neuroinflammation 2011, 8:172  doi:10.1186/1742-2094-8-172

Published: 7 December 2011

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.

Keywords:
Metallothionein; cryolesion; brain injury; alternatively activated macrophages