Increased circulating leukocyte numbers and altered macrophage phenotype correlate with the altered immune response to b
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JOURNAL OF NEUROINFLAMMATION
RESEARCH
Open Access
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 Pankhurst1,2*, William Bennett1, Matthew TK Kirkcaldie3, Adrian K West1 and Roger S Chung1
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
Background Metallothionein (MT) is a 6-7 kDa, cysteine-rich, zincbinding protein that has antioxidant properties. MT-I and MT-II are similar isoforms, often considered to behave as one species (MT-I/II), that share the ability to provide protection to the injured brain. During insult to the central nervous system (CNS), metallothionein-I and * Correspondence: [email protected] 1 Menzies Research Institute Tasmania, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania, Australia Full list of author information is available at the end of the article
-II double knockout (MT-I/II-/-) mice show increased neuron death or larger injury size after brain injury [1-3]. This firmly suggests that the presence of MT-I/II provides protection against CNS perturbation but the precis
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