Abstract
BackgroundCerebral ischemia activates both the innate and the adaptive immune response, the latter being activated within days after the stroke onset and triggered by the recognition of foreign antigens.MethodsIn this study we have investigated the phenotype of antigen presenting cells and the levels of associated major histocompatibility complex class II (MHC II) molecules in the postischemic brain after transient occlusion of the middle cerebral artery (tMCAO) followed by levodopa/benserazide treatment. Male Sprague Dawley rats were subjected to tMCAO for 105 minutes and received levodopa (20 mg/kg)/benserazide (15 mg/kg) for 5 days starting on day 2 after tMCAO. Thereafter, immune cells were isolated from the ischemic and contralateral hemisphere and analyzed by flow cytometry. Complementarily, the spatiotemporal profile of MHC II-positive (MHC II+) cells was studied in the ischemic brain during the first 30 days after tMCAO; protein levels of MHC II and the levels of inflammation associated cytokines were determined in the ischemic hemisphere.ResultsWe found that microglia/macrophages represent the main MHC II expressing cell in the postischemic brain one week after tMCAO. No differences in absolute cell numbers were found between levodopa/benserazide and vehicle-treated animals. In contrast, MHC II protein levels were significant downregulated in the ischemic infarct core by levodopa/benserazide treatment. This reduction was accompanied by reduced levels of IFN-γ, TNF-α and IL-4 in the ischemic hemisphere. In the contralateral hemisphere, we exclusively detected MHC II+ cells in the corpus callosum. Interestingly, the number of cells was increased by treatment with levodopa/benserazide independent from the infarct size 14 days after tMCAO.ConclusionsResults suggest that dopamine signaling is involved in the adaptive immune response after stroke and involves microglia/macrophages.
Highlights
Cerebral ischemia activates both the innate and the adaptive immune response, the latter being activated within days after the stroke onset and triggered by the recognition of foreign antigens
Dynamics of MHC major histocompatibility complex class II (II)+ cells in the postischemic brain after levodopa/benserazide treatment To evaluate the spatiotemporal expression of immune cell accumulation rats were subjected to Transient rat middle cerebral artery occlusion (tMCAO) for 105 minutes and at different time points coronal sections were stained for major histocompatibility complex class II (MHC II), a protein expressed on different immune cell populations [25]
Among other cell types [15,16], dopamine 1 (D1) receptors are expressed on a number of MHC II+ cells in the ischemic territory (Figure 3A) strongly suggesting that MHC II cells are regulated by treatment with levodopa
Summary
Cerebral ischemia activates both the innate and the adaptive immune response, the latter being activated within days after the stroke onset and triggered by the recognition of foreign antigens. In addition to the ischemic lesion, disruption of neuronal tracts between lesioned and remote brain areas ipsi- and contralateral to the lesioned hemisphere have a significant impact on recovery [7]. These include interhemispheric connections through the corpus callosum (CC). Disruption of neuronal circuits may go along with delayed degeneration of axonal fibers and possibly with an immune cell response [9] This idea is supported by studies showing the presence of MHC II+ cells in white matter tracts in association with degenerating myelinated axons following injury [5,10]. It has been shown that immunoreactivity to myelin basic protein is increased in lymphoid organs of stroke patients which was correlated with worse outcome [11]
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