Abstract
BackgroundConverging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion.Methodology/Principal FindingsWe show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8+ cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model.Conclusion/SignificanceCD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.
Highlights
Inflammation plays an important role in infections to fight pathogens, but can be detrimental in autoimmune diseases and ischemia-reperfusion injury
CD38, which is widely expressed on hematopoetic as well as non-hematopoetic cells, catalyzes the production of second messengers (i.e cyclic adenosine dinucleotide phosphoribose, adenosine dinucleotide phosphoribose (ADPR), nicotinic acid adenine dinucleotide phosphate (NAADP)), which act as potent intracellular calcium mobilizing agents [5,6,7,8]
Wildtype and CD382/2 displayed increased levels of MCP-1, but the increase was significantly lower in CD382/2 mice at 6 and 24 hours after temporary middle cerebral artery occlusion (tMCAO) compared with wildtype mice, while TNF-a and IFN-c concentrations in the brain were unaltered throughout this time period
Summary
Inflammation plays an important role in infections to fight pathogens, but can be detrimental in autoimmune diseases and ischemia-reperfusion injury. In addition to its enzymatic function, CD38 has been suggested to act as a receptor interacting with CD31 on endothelial cells to sustain adhesion and rolling of lymphocytes. These functions of CD38 as ectoenzyme and receptor have been implicated to mediate the humoral and innate immune response of lymphoid and myeloid lineage cells [5,9]. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. We investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion
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