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.
Highlights
Sepsis represented one of the major causes of death until the discovery of antibiotics in the early 20th century
In order to test whether the observed increase in caspase-8 activity was required for monocyte activation, we pretreated THP-1 cells with the specific caspase-8 inhibitor IETD-fmk for 30 minutes prior to LPS challenge
Monocytes have been described to play an essential role in the development of systemic inflammatory response syndrome (SIRS), since they are capable of modulating the innate immune response [8, 37]
Summary
Sepsis represented one of the major causes of death until the discovery of antibiotics in the early 20th century Emerging diseases such as Ebola, H5N1 avian influenza or SARS, together with an increase in antibiotic resistance in previously controllable pathogens such as Mycobacterium tuberculosis or MRSA have led to sepsis once again becoming a global burden [1, 2]. This is due to the high mortality rates associated to severe sepsis, ranging from 20% to 80% in the event of a systemic inflammatory response syndrome (SIRS). Given the positive feedback nature of the resultant response, the irreversible cytokine storm can continue even after the clearance of any pathogen, complicating the treatment and worsening the prognosis [4, 11]
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