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.
Highlights d Deletion of caspase-11 prevents disseminated intravascular coagulation (DIC) in sepsis d Deletion of GSDMD prevents caspase-11-and TF-mediated DIC in endotoxemia d GSDMD deficiency inhibits endotoxin-induced TF activation by reducing PS exposure d Activation of GSDMD by caspase-11 triggers Ca 2+dependent PS exposure through TMEM16F
High mobility group box 1 (HMGB1) is an evolutionarily conserved protein, and constitutively expressed in virtually all types of cells. Infection and injury converge on common inflammatory responses that are mediated by HMGB1 secreted from immunologically activated immune cells or passively released from pathologically damaged cells. Herein we review the emerging molecular mechanisms underlying the regulation of pathogen-associated molecular patterns (PAMPs)-induced HMGB1 secretion, and summarize many HMGB1-targeting therapeutic strategies for the treatment of infection- and injury-elicited inflammatory diseases. It may well be possible to develop strategies that specifically attenuate damage-associated molecular patterns (DAMPs)-mediated inflammatory responses without compromising the PAMPs-mediated innate immunity for the clinical management of infection- and injury-elicited inflammatory diseases.
Magnesium calcium phosphate biocement (MCPB) with rapid-setting characteristics was fabricated by using the mixed powders of magnesium oxide (MgO) and calcium dihydrogen phosphate (Ca(H 2 PO 4 ) 2 . H 2 O). The results revealed that the MCPB hardened after mixing the powders with water for about 7 min, and the compressive strength reached 43 MPa after setting for 1 h, indicating that the MCPB had a short setting time and high initial mechanical strength. After the acid -base reaction of MCPB containing MgO and Ca(H 2 PO 4 ) 2 . H 2 O in a molar ratio of 2 : 1, the final hydrated products were Mg 3 (PO 4 ) 2 and Ca 3 (PO 4 ) 2 . The MCPB was degradable in Tris-HCl solution and the degradation ratio was obviously higher than calcium phosphate biocement (CPB) because of its fast dissolution. The attachment and proliferation of the MG 63 cells on the MCPB were significantly enhanced in comparison with CPB, and the alkaline phosphatase activity of MG 63 cells on the MCPB was significantly higher than on the CPB at 7 and 14 days. The MG 63 cells with normal phenotype spread well on the MCPB surfaces, and were attached in close proximity to the substrate, as seen by scanning electron microscopy (SEM). The results demonstrated that the MCPB had a good ability to support cell attachment, proliferation and differentiation, and exhibited good cytocompatibility.
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