LPS Induces Active HMGB1 Release From Hepatocytes Into Exosomes Through the Coordinated Activities of TLR4 and Caspase-11/GSDMD Signaling

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.

[1]  Simon C Watkins,et al.  The Endotoxin Delivery Protein HMGB1 Mediates Caspase‐11‐Dependent Lethality in Sepsis , 2018, Immunity.

[2]  N. Nieto,et al.  High‐Mobility Group Box‐1 and Liver Disease , 2018, Hepatology communications.

[3]  E. Park,et al.  Degradation of histone deacetylase 4 via the TLR4/JAK/STAT1 signaling pathway promotes the acetylation of high mobility group box 1 (HMGB1) in lipopolysaccharide‐activated macrophages , 2018, FEBS open bio.

[4]  D. Stolz,et al.  Interferon regulatory factor 1–Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury , 2018, Hepatology.

[5]  A. Malik,et al.  Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury , 2017, The Journal of clinical investigation.

[6]  Y. Sadovsky,et al.  Isolation of human trophoblastic extracellular vesicles and characterization of their cargo and antiviral activity. , 2016, Placenta.

[7]  Dacheng Wang,et al.  Erratum: Pore-forming activity and structural autoinhibition of the gasdermin family , 2016, Nature.

[8]  V. Dixit,et al.  GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes , 2016, Proceedings of the National Academy of Sciences.

[9]  Ishita Banerjee,et al.  Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation , 2016, Cell.

[10]  Christopher W Seymour,et al.  Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[11]  Chuan-Qi Zhong,et al.  Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion , 2015, Cell Research.

[12]  S. Kummerfeld,et al.  Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling , 2015, Nature.

[13]  T. Cai,et al.  Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death , 2015, Nature.

[14]  T. Billiar,et al.  Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling , 2015, Science Signaling.

[15]  Haichao Wang,et al.  HMGB1 in health and disease. , 2014, Molecular aspects of medicine.

[16]  T. Billiar,et al.  High‐mobility group box‐1 in sterile inflammation , 2014, Journal of internal medicine.

[17]  C. Théry,et al.  Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. , 2014, Annual review of cell and developmental biology.

[18]  P. Li,et al.  Inflammatory caspases are innate immune receptors for intracellular LPS , 2014, Nature.

[19]  B. Ratliff,et al.  High mobility group box 1 is a novel deacetylation target of Sirtuin1 , 2014, Kidney international.

[20]  D. Bumann,et al.  Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases , 2014, Nature.

[21]  K. Tracey,et al.  JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation , 2014, Proceedings of the National Academy of Sciences.

[22]  D. Powell,et al.  Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock , 2013, Science.

[23]  Jiangxia Liu,et al.  Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity , 2013, Nature Immunology.

[24]  D. Stolz,et al.  Cellular‐specific role of toll‐like receptor 4 in hepatic ischemia‐reperfusion injury in mice , 2013, Hepatology.

[25]  S. Chien,et al.  Ca2+/calmodulin-dependent protein kinase kinase β phosphorylation of Sirtuin 1 in endothelium is atheroprotective , 2013, Proceedings of the National Academy of Sciences.

[26]  Simon C Watkins,et al.  Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis , 2013, The Journal of Immunology.

[27]  Ziying Wang,et al.  HDAC4/5-HMGB1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury , 2013, Journal of cellular and molecular medicine.

[28]  K. Oh,et al.  Calcium/Calmodulin-Dependent Protein Kinase is Involved in the Release of High Mobility Group Box 1 Via the Interferon-β Signaling Pathway , 2012, Immune network.

[29]  Jinfeng Liu,et al.  Non-canonical inflammasome activation targets caspase-11 , 2011, Nature.

[30]  T. Billiar,et al.  Interferon Regulatory Factor 1 Mediates Acetylation and Release of High Mobility Group Box 1 from Hepatocytes During Murine Liver Ischemia-Reperfusion Injury , 2011, Shock.

[31]  Jason P. Zlotnicki,et al.  High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity* , 2010, The Journal of Biological Chemistry.

[32]  T. Billiar,et al.  Hepatocytes express functional NOD1 and NOD2 receptors: a role for NOD1 in hepatocyte CC and CXC chemokine production. , 2010, Journal of hepatology.

[33]  D. Pisetsky,et al.  The translocation of HMGB1 during cell activation and cell death , 2009, Autoimmunity.

[34]  T. Billiar,et al.  β2-Integrin-induced p38 MAPK Activation Is a Key Mediator in the CD14/TLR4/MD2-dependent Uptake of Lipopolysaccharide by Hepatocytes* , 2008, Journal of Biological Chemistry.

[35]  D. Angus,et al.  Calcium/Calmodulin-Dependent Protein Kinase (CaMK) IV Mediates Nucleocytoplasmic Shuttling and Release of HMGB1 during Lipopolysaccharide Stimulation of Macrophages1 , 2008, The Journal of Immunology.

[36]  M. Rosengart,et al.  HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signaling , 2007, The Journal of experimental medicine.

[37]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[38]  G. Su,et al.  HEPATOCYTES ENHANCE EFFECTS OF LIPOPOLYSACCHARIDE ON LIVER NONPARENCHYMAL CELLS THROUGH CLOSE CELL INTERACTIONS , 2005, Shock.

[39]  K. Tracey,et al.  Reversing established sepsis with antagonists of endogenous high-mobility group box 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Weiss.  Faculty Opinions recommendation of Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. , 2003 .

[41]  K. Fukase,et al.  Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2 , 2003, The Journal of experimental medicine.

[42]  J. Vincent,et al.  Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[43]  M. Abreu,et al.  Decreased Expression of Toll-Like Receptor-4 and MD-2 Correlates with Intestinal Epithelial Cell Protection Against Dysregulated Proinflammatory Gene Expression in Response to Bacterial Lipopolysaccharide1 , 2001, The Journal of Immunology.

[44]  K. Tracey,et al.  HMG-1 as a late mediator of endotoxin lethality in mice. , 1999, Science.

[45]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[46]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[47]  G. Koch.  The endoplasmic reticulum and calcium storage , 1990, BioEssays : news and reviews in molecular, cellular and developmental biology.

[48]  R. Schwabe,et al.  The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. , 2015, The Journal of clinical investigation.

[49]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.