A Critical Role for Human Caspase-4 in Endotoxin Sensitivity

Abstract

Response to endotoxins is an important part of the organismal reaction to gram-negative bacteria, and plays a critical role in sepsis and septic shock, as well as other conditions such as metabolic endotoxemia. Humans are generally more sensitive to endotoxins when compared to experimental animals such as mouse. Inflammatory caspases mediate endotoxin-induced interelukin-1β (IL-1β) secretion and lethality in mouse, and caspase-4 is an inflammatory caspase that is found in the human, and not mouse, genome. To test whether caspase-4 is involved in endotoxin sensitivity, we developed a transgenic mouse expressing human caspase-4 in its genomic context. Caspase-4 transgenic mice exhibited significantly higher endotoxin sensitivity, as measured by enhanced cytokine secretion and lethality following lipopolysaccharide (LPS) challenge. Using bone marrow-derived macrophages (BMDMs), we then observed that caspase-4 can support activation of caspase-1 and secretion of IL-1β and IL-18 in response to priming signals (LPS or Pam3CSK4) alone, without the need for second signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by human caspase-4 could represent unique mechanism in humans, as compared to laboratory rodents, and may partially explain the higher sensitivity to endotoxins observed in humans. Regulation of the expression, activation, or activity of caspase-4 therefore represent therapeutic targets for systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and related disorders.

Silver Nanoparticles Induce Degradation of the Endoplasmic Reticulum Stress Sensor Activating Transcription Factor-6 Leading to Activation of the NLRP-3 Inflammasome

“…54). Nevertheless, to date, only a few studies reported the potential involvement of caspase-4 in the activation of the inflammasomes (30,55). Our results indicate that caspase-4 is indeed required for the priming of the inflammasome, as the absence of this caspase resulted in a severe impairment of pro-IL-1␤ synthesis.…”

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

“…Consumption of high-fat diet has been shown to induce an increase in the level of blood LPS in mice and humans (and likely endogenous oxidatively modified lipids as well), leading to metabolic endotoxemia, and insulin resistance (81)(82)(83)(84). Since caspase-4 is expressed in peripheral immune cells such as macrophages (27), it is tempting to speculate that caspase-4 in part mediates such response to peripheral endotoxemia.…”

“…Recently, we reported on the development and characterization of a novel transgenic mouse expressing human caspase-4 from its native regulatory elements. In these studies, we observed a crucial role for caspase-4 in not only initiating inflammatory cell death but also priming the Nlrp3 inflammasome and caspase-1 activation (27). Caspase-4 is an intracellular receptor for LPS leading to an induction of pyroptosis (28) by cleaving gusdermin D (29,30), and activates the non-canonical Nlrp3 inflammasome leading to activation of caspase-1 and secretion of IL-1b and IL-18 (31)(32).…”

“…The APP/ PS1 (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) (stock #004462) line was purchased from The Jackson laboratory (Bar Harbor, ME, USA), and crossed with human caspase-4 transgenic mice, denoted as CASP4, which we have recently described (27). Mice were genotyped by quantitative PCR using the Universal Probe Library (UPL; Roche Applied Science, Indianapolis, IN, USA) (Supplementary Material, Table S3).…”

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“…The limited literature on these human caspases suggests their activation by intracellular pathogens, and proposes functions in triggering IL-18 production and pyroptosis in infected epithelial cells [21]. Studies from a transgenic mouse expressing human caspase-4 implicated this caspase, like murine caspase-11, as an important mediator of endotoxin sensitivity [22]. The evolution of multiple inflammatory caspases capable of pyroptosis initiation highlights the importance of this process as an anti-microbial defence strategy.…”