title: Spatio-temporal activation of caspase-8 in myeloid cells upon ischemic stroke.
abstract: Ischemic stroke (caused by thrombosis, embolism or vasoconstriction) lead to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral macrophages, which contribute to an inflammatory response involved in regulation of the neuronal damage. We showed earlier that upon pro-inflammatory stimuli, the orderly activation of caspase-8 and caspase-3/7 regulates microglia activation through a protein kinase C-δ dependent pathway. Here, we present in vivo evidence for the activation of caspase-8 and caspase-3 in microglia/macrophages in post-mortem tissue from human ischemic stroke subjects. Indeed, CD68-positive microglia/macrophages in the ischemic peri-infarct area exhibited significant expression of the cleaved and active form of caspase-8 and caspase-3. The temporal and spatial activation of caspase-8 was further investigated in a permanent middle cerebral artery occlusion mouse model of ischemic stroke. Increasing levels of active caspase-8 was found in Iba1-positive cells over time in the peri-infarct area, at 6, 24 and 48 h after artery occlusion. Analysis of post-mortem brain tissue from human subject who suffered two stroke events, referred as recent and old stroke, revealed that expression of cleaved caspase-8 and -3 in CD68-positive cells could only be found in the recent stroke area. Analysis of cleaved caspase-8 and -3 expressions in a panel of human stroke cases arranged upon days-after stroke and age-matched controls suggested that the expression of these caspases correlated with the time of onset of stroke. Collectively, these data illustrate the temporal and spatial activation of caspase-8 and -3 in microglia/macrophages occurring upon ischemic stroke and suggest that the expression of these caspases could be used in neuropathological diagnostic work.
authors: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors: Johanna
authors: J
authors: Rodhe
authors: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors: Miguel A
authors: MA
authors: Burguillos
authors: Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41012, Sevilla, Spain.
authors: Rocio M
authors: RM
authors: de Pablos
authors: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors: Edel
authors: E
authors: Kavanagh
authors: Department of Clinical Sciences, Division of Oncology and Pathology, Department of Neuropathology, Lund University, Lund, Sweden.
authors: Annette
authors: A
authors: Persson
authors: Department of Clinical Sciences, Division of Oncology and Pathology, Department of Neuropathology, Lund University, Lund, Sweden.
authors: Elisabet
authors: E
authors: Englund
authors: Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Tomas
authors: T
authors: Deierborg
authors: Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41012, Sevilla, Spain.
authors: Jose L
authors: JL
authors: Venero
authors: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden. Bertrand.Joseph@ki.se.
authors: Bertrand
authors: B
authors: Joseph
mesh_terms: D000208:Acute Disease; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D022423:Myeloid Cells / Q000201:enzymology* / Q000473:pathology; D020521:Stroke / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D053181:Caspase 8; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; C112986:AIF1 protein, human; C491049:Aif1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C081026:CD68 protein, mouse; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse
keywords: Caspase-3; Caspase-8; Human brain tissue; Ischemic stroke; Macrophage; Microglia; Spatio-temporal activation; pMCAO model