1. Caspase-8 inhibition represses initial human monocyte activation in septic shock model
- Author
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Johanna Rodhe, José Antonio Pérez-Simón, Teresa Caballero-Velázquez, Luis Ignacio Sánchez-Abarca, Antonio J. Herrera, José L. Venero, Alejandro Carrillo-Jimenez, P Vlachos, Maria Jose Oliva-Martin, Bertrand Joseph, Albert García-Quintanilla, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (España), European Commission, Swedish Research Council, Swedish Childhood Cancer Foundation, Swedish Cancer Society, Swedish Parkinson Foundation, Swedish Brain Foundation, [Jose Oliva-Martin, Maria] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Carrillo-Jimenez, Alejandro] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Herrera, Antonio] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Garcia-Quintanilla, Albert] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Luis Venero, Jose] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Oliva-Martin, Maria] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Rodhe, Johanna] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Vlachos, Pinelopi] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Joseph, Bertrand] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Jose Oliva-Martin, Maria] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Sanchez-Abarca, Luis Ignacio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Caballero-Velazquez, Teresa] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Perez-Simon, Jose Antonio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, SwedenHosp Univ Virgen del Rocio, Dept Haematol, Malaga, Spain, MINECO/FEDER, UE, Junta of Andalucia, and Swedish Cancer Foundation
- Subjects
0301 basic medicine ,Monocyte ,Monocytes ,caspase-8 ,sepsis ,Mice ,Mechanisms ,Il-1-beta ,Cells, Cultured ,Caspase ,Mice, Knockout ,Caspase 8 ,biology ,Pro-inflammatory activation ,Switch ,Caspase Inhibitors ,Shock, Septic ,Cell biology ,medicine.anatomical_structure ,Oncology ,Necroptosis ,monocyte ,Cytokines ,medicine.symptom ,Cell activation ,Caspase-8 ,Programmed cell death ,Macrophage differentiation ,necroptosis ,Inflammation ,03 medical and health sciences ,Sepsis ,Pathology Section ,medicine ,Animals ,Humans ,Septic shock ,medicine.disease ,Research Paper: Pathology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,inflammation ,Immunology ,biology.protein ,Surviving sepsis ,Cell-death - 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., This work was supported by grants SAF2012-39029 and SAF2015-64171R (MINECO/FEDER, UE), the Junta of Andalucía (P10-CTS-6494), the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Foundation, Swedish Parkinson Foundation and the Swedish Brain Foundation.
- Published
- 2016