RT Journal Article
T1 Caspase-8 inhibition represses initial human monocyte activation in septic shock model.
A1 Oliva-Martin, Maria Jose
A1 Sanchez-Abarca, Luis Ignacio
A1 Rodhe, Johanna
A1 Carrillo-Jimenez, Alejandro
A1 Vlachos, Pinelopi
A1 Herrera, Antonio Jose
A1 Garcia-Quintanilla, Albert
A1 Caballero-Velazquez, Teresa
A1 Perez-Simon, Jose Antonio
A1 Joseph, Bertrand
A1 Venero, Jose Luis
K1 Pathology Section
K1 caspase-8
K1 inflammation
K1 monocyte
K1 necroptosis
K1 sepsis
AB 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.
PB Impact Journals LLC
YR 2016
FD 2016-05-16
LK http://hdl.handle.net/10668/10141
UL http://hdl.handle.net/10668/10141
LA en
NO Oliva-Martin MJ, Sanchez-Abarca LI, Rodhe J, Carrillo-Jimenez A, Vlachos P, Herrera AJ, et al. Caspase-8 inhibition represses initial human monocyte activation in septic shock model. Oncotarget. 2016 Jun 21;7(25):37456-37470.
NO We acknowledge Mr. Joshua Long for a thorough and comprehensive proof-editing of this manuscript. 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.
DS RISalud
RD Apr 8, 2025