title: CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.
abstract: BACKGROUND
  Converging 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  CD38 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.
authors.affiliation: Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. cchoe@uke.de
authors.forename: Chi-un
authors.initials: CU
authors.lastname: Choe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lardong
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.forename: Peter
authors.initials: P
authors.lastname: Ludewig
authors.forename: Frank
authors.initials: F
authors.lastname: Leypoldt
authors.forename: Friedrich
authors.initials: F
authors.lastname: Koch-Nolte
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D001930:Brain Injuries / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002545:Brain Ischemia / Q000209:etiology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1