2026-04-29T20:47:12Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/252092025-05-07T09:32:45Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927

00925njm 22002777a 4500 dc Oliva-Martin, Maria Jose author Sanchez-Abarca, Luis Ignacio author Rodhe, Johanna author Carrillo-Jimenez, Alejandro author Vlachos, Pinelopi author Herrera, Antonio Jose author Garcia-Quintanilla, Albert author Caballero-Velazquez, Teresa author Perez-Simon, Jose Antonio author Joseph, Bertrand author Venero, José Luis author 2016 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-1? 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. 10.18632/oncotarget.9648 1949-2553 Oncotarget http://hdl.handle.net/10668/10141 27250033 https://hdl.handle.net/20.500.12105/25209 Pathology Section Caspase-8 Inflammation Monocyte Necroptosis Sepsis Caspase-8 inhibition represses initial human monocyte activation in septic shock model