The role of nuclear macromolecules in innate immunity.

Nuclear macromolecules, in addition to their intracellular role in regulating cell function, can translocate into the extracellular space where they can activate innate immunity. This translocation can occur in various settings and reflects the dynamic nature of nuclear structure. Of nuclear molecules, DNA and the DNA-binding protein, HMGB1, display distinct patterns of immune activity. For DNA, immune activity depends on sequence, base methylation, and context. While bacterial DNA is an immune activator, mammalian DNA is either inert or inhibitory when free. In contrast, mammalian DNA in the form of immune complexes can trigger immune cell activation. As shown in in vivo and in vitro studies, DNA can exit cells during apoptotic as well as necrotic cell death in a process that may depend on the presence of macrophages. Like DNA, HMGB1 can exit cells and acquire immune properties. For HMGB1, the translocation occurs in macrophages that have been stimulated by Toll-like receptor (TLR) ligands as well as cytokines; HMGB1 release can also occur with apoptotic as well as necrotic death. While HMGB1 alone can display cytokine activity, it may also activate cells in conjunction with other immune stimulators such as TLR ligands. For both DNA and HMGB1, the immune properties may therefore reflect the array of other endogenous as well as exogenous molecules present.

[1]  H. Rauvala,et al.  Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). , 2007, Journal of leukocyte biology.

[2]  Jeon-Soo Shin,et al.  Nucleocytoplasmic Shuttling of HMGB1 Is Regulated by Phosphorylation That Redirects It toward Secretion1 , 2006, The Journal of Immunology.

[3]  D. Pisetsky,et al.  The extracellular release of HMGB1 during apoptotic cell death. , 2006, American journal of physiology. Cell physiology.

[4]  H. Harris,et al.  Alarmin(g) news about danger , 2006, EMBO reports.

[5]  L. Rönnblom,et al.  The type I interferon system in systemic lupus erythematosus. , 2006, Arthritis and rheumatism.

[6]  D. Pisetsky,et al.  The binding of sera of patients with SLE to bacterial and mammalian DNA. , 2006, Clinical immunology.

[7]  S. Akira,et al.  Toll-like receptor–independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation , 2005, The Journal of experimental medicine.

[8]  D. Pisetsky,et al.  The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells , 2005, Immunology.

[9]  B. Cookson,et al.  Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells , 2005, Infection and Immunity.

[10]  D. Pisetsky,et al.  The effect of inflammation on the generation of plasma DNA from dead and dying cells in the peritoneum , 2005, Journal of leukocyte biology.

[11]  D. Golenbock,et al.  Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. , 2005, The Journal of clinical investigation.

[12]  U. Andersson,et al.  RAGE is the Major Receptor for the Proinflammatory Activity of HMGB1 in Rodent Macrophages , 2005, Scandinavian journal of immunology.

[13]  D. Pisetsky,et al.  Release of DNA from Dead and Dying Lymphocyte and Monocyte Cell Lines In Vitro , 2004, Scandinavian journal of immunology.

[14]  H. Wagner.  The immunobiology of the TLR9 subfamily. , 2004, Trends in immunology.

[15]  D. Pisetsky,et al.  The effect of dexamethasone on the generation of plasma DNA from dead and dying cells. , 2004, The American journal of pathology.

[16]  D. Pisetsky,et al.  Mechanisms of activation of the RAW264.7 macrophage cell line by transfected mammalian DNA. , 2004, Cellular immunology.

[17]  M. Shlomchik,et al.  Activation of autoreactive B cells by CpG dsDNA. , 2003, Immunity.

[18]  Tiziana Bonaldi,et al.  Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion , 2003, The EMBO journal.

[19]  D. Pisetsky,et al.  Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. , 2003, Blood.

[20]  K. Tracey,et al.  Activation of gene expression in human neutrophils by high mobility group box 1 protein. , 2003, American journal of physiology. Cell physiology.

[21]  T. Misteli,et al.  Release of chromatin protein HMGB1 by necrotic cells triggers inflammation , 2002, Nature.

[22]  K. Tracey,et al.  HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. , 2002, Cytokine.

[23]  D. Pisetsky,et al.  Inhibition of murine macrophage nitric oxide production by synthetic oligonucleotides , 2002, Journal of leukocyte biology.

[24]  Y. Lo,et al.  Circulating DNA in Plasma and Serum: Biology, Preanalytical Issues and Diagnostic Applications , 2002, Clinical chemistry and laboratory medicine.

[25]  S. Müller,et al.  The double life of HMGB1 chromatin protein: architectural factor and extracellular signal , 2001 .

[26]  J. O. Thomas,et al.  HMG1 and 2: architectural DNA-binding proteins. , 2001, Biochemical Society transactions.

[27]  Philippa Marrack,et al.  Autoimmune disease: why and where it occurs , 2001, Nature Medicine.

[28]  K. Tracey,et al.  High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes , 2000, The Journal of experimental medicine.

[29]  D. Sidransky.  Circulating DNA: What We Know and What We Need to Learn , 2000 .

[30]  L. Rönnblom,et al.  Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. , 1999, Journal of immunology.

[31]  D. Pisetsky,et al.  Specificity of antibodies to bacterial DNA in the sera of healthy human subjects and patients with systemic lupus erythematosus. , 1999, The Journal of rheumatology.

[32]  Michael Bustin,et al.  Regulation of DNA-Dependent Activities by the Functional Motifs of the High-Mobility-Group Chromosomal Proteins , 1999, Molecular and Cellular Biology.

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

[34]  D. Pisetsky.  Antibody Responses to DNA in Normal Immunity and Aberrant Immunity , 1998, Clinical Diagnostic Laboratory Immunology.

[35]  D. Pisetsky,et al.  Specificity and immunochemical properties of antibodies to bacterial DNA in sera of normal human subjects and patients with systemic lupus erythematosus (SLE) , 1997, Clinical and experimental immunology.

[36]  D. Pisetsky,et al.  Deficient expression of antibodies specific for bacterial DNA by patients with systemic lupus erythematosus. , 1997, Proceedings of the Association of American Physicians.

[37]  D. Pisetsky.  Immune activation by bacterial DNA: a new genetic code. , 1996, Immunity.

[38]  B. Kotzin.  Systemic Lupus Erythematosus , 1996, Cell.

[39]  D. Pisetsky,et al.  Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA , 1996, The Journal of experimental medicine.

[40]  E. Tan,et al.  Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. , 1989, Advances in immunology.

[41]  F. Vogel,et al.  Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection. , 1988, Biochimica et biophysica acta.