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

<p>Abstract</p> <p>Background</p> <p>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 <it>in vitro </it>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p