title: Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.
abstract: Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele ofCASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, 171 76 Stockholm, Sweden.|Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013-Sevilla, Spain.
authors.forename: Edel
authors.initials: E
authors.lastname: Kavanagh
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Burguillos
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013-Sevilla, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carrillo-Jimenez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013-Sevilla, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Oliva-Martin
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013-Sevilla, Spain.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Santiago
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rodhe
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Joseph
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013-Sevilla, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Venero
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics*; D059290:Dopaminergic Neurons; D005911:Gliosis / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020267:MPTP Poisoning / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D017628:Microglia / Q000473:pathology*; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D022423:Myeloid Cells / Q000201:enzymology*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009113:Muramidase; C505526:Casp8 protein, mouse; D053181:Caspase 8
keywords: Caspace-8; MPTP; Parkinson's disease; lipopolysaccharide; microglia