The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis

Abstract

Summary Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, a lytic form of cell death. Caspase-11-dependent pyroptosis mediates lethality in endotoxemia, but it is unclear how LPS is delivered into the cytosol for the activation of caspase-11. Here we discovered that hepatocyte-released high mobility group box 1 (HMGB1) was required for caspase-11-dependent pyroptosis and lethality in endotoxemia and bacterial sepsis. Mechanistically, hepatocyte-released HMGB1 bound LPS and targeted its internalization into the lysosomes of macrophages and endothelial cells via the receptor for advanced glycation end-products (RAGE). Subsequently, HMGB1 permeabilized the phospholipid bilayer in the acidic environment of lysosomes. This resulted in LPS leakage into the cytosol and caspase-11 activation. Depletion of hepatocyte HMGB1, inhibition of hepatocyte HMGB1 release, neutralizing extracellular HMGB1, or RAGE deficiency prevented caspase-11-dependent pyroptosis and death in endotoxemia and bacterial sepsis. These findings indicate that HMGB1 interacts with LPS to mediate caspase-11-dependent pyroptosis in lethal sepsis.

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…20 LPS may also be delivered into the cytoplasm by outer membrane vesicles and high-mobility group box-1 protein (HMGB1). 21,22 Similar to LPS, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC), an oxidized phospholipid, and lipophosphoglycan produced by Leishmania species have been suggested to activate caspase-11; however, conflicting findings have been reported. [23][24][25][26] The fungal pathogens Aspergillus fumigatus and Paracoccidioides brasiliensis have also been demonstrated to activate the noncanonical inflammasome.…”

“…20,21 Circulating LPS is also delivered into the cytosol in an HMGB1dependent manner, leading to the activation of the noncanonical inflammasome. 22 Activated inflammatory caspases induce pyroptosis by activating GSDMD. Pyroptosis is considered to contribute to the pathology of endotoxemia through the release of DAMPs.…”

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

“…To date, the lectin CD205, also named DEC-205 or Clec13B, has been described as a receptor for CpG ODN on dendritic cells and B cells, 19 allowing delivery to intracellular TLR9 to engage specific signaling pathways. 12,21 In analogy, we hypothesized that CD93 may favor the shuttling of exogenous DNA towards TLR9. Of note, it has been previously shown that neurons can express CD93 during inflammatory processes such as ischemia encephalitis 20 DEC-205 also contains a CTLD which is involved in the surface binding and uptake of CpG ODN and bacterial DNA.…”

“…Interestingly, it has already been shown that CD93 can promote TLR signaling and particularly increase LPS recognition by TLR4 and can boost the inflammatory response of monocytes. 12,21 In analogy, we hypothesized that CD93 may favor the shuttling of exogenous DNA towards TLR9. Using several assays, we herein showed an interaction between either the bacterial DNA or class A CpG ODN with the CTLD of CD93.…”

Leukocyte-derived High-mobility group box 1 controls innate immune responses against Listeria monocytogenes

“…High-mobility group box 1 (HMGB1) is an abundantly expressed nucleoprotein and considered a prototypical damage-associated molecular pattern (DAMP) with key roles in the initiation of post-necrotic inflammation in various tissues including the skin (3), liver (4,5), pancreas (6,7), skeletal and cardiac muscle (8,9), and central nervous system (10). Moreover, neutralization of extracellular HMGB1 was shown to alleviate LPS-induced septic shock and reduce lethality in polymicrobial abdominal sepsis (11–13), indicating that HMGB1 neutralization may be uniformly beneficial during both sterile and infectious inflammatory processes. Consequently, HMGB1 has repeatedly been suggested as a promising therapeutic target for infectious and non-infectious inflammatory diseases (14–16).…”