Abstract
High-mobility group box-1 (HMGB1), a ubiquitous nuclear protein, acts as a late mediator of lethality when released extracellularly during sepsis. The major source of circulating HMGB1 in sepsis is hepatocytes. However, the mechanism of HMGB1 release of hepatocytes during sepsis is not very clear. We have previously shown that bacterial endotoxin [lipopolysaccharide (LPS)] sensing pathways, including Toll-like receptor (TLR)4 and caspase-11, regulate hepatocyte HMGB1 release in response to LPS. Here, we report the novel function of caspase-11 and gasdermin D (GsdmD) in LPS-induced active HMGB1 released from hepatocytes. HMGB1 release during endotoxemia was caspase-11/GsdmD dependent via an active way in vivo and in vitro. Caspase-11/GsdmD was responsible for HMGB1 translocation from nucleus to the cytoplasm via calcium changing-induced phosphorylation of calcium-calmodulin kinase kinase (camkk)β during endotoxemia. Cleaved GsdmD accumulated on the endoplasmic reticulum, suggesting this may lead to calcium leak and intracellular calcium increase. Furthermore, we investigated that exosome was an important pathway for HMGB1 release from hepatocytes; this process was dependent on TLR4, independent of caspase-11 and GsdmD in vivo and in vitro. These findings provide a novel mechanism that TLR4 signaling results in an increase in caspase-11 expression, as well as increased exosome release, while caspase-11/GsdmD activation/cleavage leads to accumulation of HMGB1 in the cytoplasm through a process associated with the release of calcium from the endoplasmic reticulum and camkkβ activation.
Highlights
Sepsis is a dysregulated inflammatory and metabolic state associated with infection
We have previously demonstrated that hepatocytes release High-mobility group box-1 (HMGB1) in sepsis and that this requires caspase-11 and gasdermin D (GsdmD) [5]
Hepatocytes are known to sense the presence of pathogen-associated molecular patterns (PAMPs) in the circulation, and the detection of PAMPs triggers the release of immune regulators such as HMGB1 or chemokines [5, 14, 32]
Summary
Sepsis is a dysregulated inflammatory and metabolic state associated with infection. This dysregulated state is associated with multi-organ dysfunction and high mortality [1]. Blocking single cytokines early in the course of sepsis has not improved outcomes during clinical trials [2] This led to the search for late mediators of lethality in sepsis, and this search yielded high-mobility group box-1 (HMGB1), a nuclear protein that is released by the liver during sepsis that can drive pyroptosis, immune dysfunction, and lethality in sepsis models [3, 4]. The intracellular steps that lead to the active release of HMGB1 by hepatocytes in response to LPS are unknown This release is known to involve Toll-like receptor (TLR)4-mediated LPS uptake by hepatocytes and is caspase dependent [5, 14]. Extracellular release of HMGB1 takes place via exosomes, and this requires receptor-specific roles for TLR4 and caspase-11/GsdmD These findings illuminate a novel pathway for the active release of HMGB1 from hepatocytes that is relevant to sepsis lethality
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