title: Caspase-8 inhibition represses initial human monocyte activation in septic shock model.
abstract: In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla (IBiS)-/CSIC/Universidad de Sevilla, Sevilla, Spain.|Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Oliva-Martin
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Luis Ignacio
authors.initials: LI
authors.lastname: Sanchez-Abarca
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS)-/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rodhe
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carrillo-Jimenez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS)-/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Pinelopi
authors.initials: P
authors.lastname: Vlachos
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Antonio Jose
authors.initials: AJ
authors.lastname: Herrera
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Garcia-Quintanilla
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Caballero-Velazquez
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Perez-Simon
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS)-/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Joseph
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Venero
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D012772:Shock, Septic / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*
chemical_list: D061945:Caspase Inhibitors; D016207:Cytokines; D053181:Caspase 8
keywords: Pathology Section; caspase-8; inflammation; monocyte; necroptosis; sepsis