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Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.

ABSTRACT: Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1-nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1beta, IL-6, IL-10, and tumor necrosis factor (TNF) alpha and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2-dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1-nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.

SUBMITTER: Urbonaviciute V

PROVIDER: S-EPMC2605236 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.

Urbonaviciute Vilma V Fürnrohr Barbara G BG Meister Silke S Munoz Luis L Heyder Petra P De Marchis Francesco F Bianchi Marco E ME Kirschning Carsten C Wagner Hermann H Manfredi Angelo A AA Kalden Joachim R JR Schett Georg G Rovere-Querini Patrizia P Herrmann Martin M Voll Reinhard E RE

The Journal of experimental medicine 20081208 13

Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box pr ...[more]

PMID: 19064698

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Project description:Background & aimsHigh mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis.MethodsWe utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses.ResultsAfter injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor κB, degradation of inhibitor of κB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor κB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection.ConclusionsIn 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.

Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1? (IL-1?), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1? axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1? signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1? antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1? signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1? ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-?B)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-?B and ultimately the depression of proinflammatory cytokine programs.ASC-mediated caspase-1/IL-1? signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1? signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.

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Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.

Publications

Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.

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