Trends in Immunology
ReviewHigh-mobility group box family of proteins: ligand and sensor for innate immunity
Section snippets
Self and nonself in the immune system: a preface
The science of immunology was born in the ravages of epidemic infectious diseases. As individuals, we live in a delicate equilibrium with microbes such as viruses and bacteria in which the immune system is crucially positioned to maintain host homeostasis. One extension of the germ theory of disease, which eventually recognized foreign microorganisms as disease-causing agents, was that the immune system must be designed to kill the pathogen and not the host. Indeed, natural selection has gone
The HMGB family proteins: a brief overview
In mammals, there are three members of the HMGB family, HMGB1, HMGB2, and HMGB3. HMGB family members have a highly conserved primary structure (>80% amino acid identity), and comprise two DNA-binding domains (HMG boxes A and B) and an acidic tail enriched with negatively charged glutamic and aspartic acid residues 11, 12, 13. The expression of HMGB1 is ubiquitous and abundant 2, 8, 14. By contrast, the expression of HMGB2 is prevalent during embryogenesis but then becomes restricted mainly to
HMGB1 as a ligand for innate receptors
HMGB1 became the focus of attention in the field of immunity after its discovery as a potent, cytokine-like instigator of inflammation 2, 8, 10, 17, 20. HMGB1, in addition to being highly expressed in the nucleus, is also present in the cytosol and extracellular fluid 2, 8, 20. Indeed, cytosolic and extracellular HMGB1 concentrations are notably increased upon cellular stimulation by immunomodulators such as DAMPs and inflammatory cytokines. HMGB1 is released via two distinct processes. First,
Synergistic interactions of HMGB1 with other cytokines and immune mediators
Although the contribution of HMGB1 to evoked inflammatory responses is well documented, whether HMGB1 per se has any ability to initiate cellular signaling has been called into question. Since the original and subsequent descriptions of HMGB1 as an instigator of inflammatory responses 2, 8, 10, 19, several reports have claimed that purified HMGB1 has little, if any, ability to induce expression of cytokines 46, 47. Although rectifying these seemingly discrepant data is beyond the scope of this
HMGB1 and its family members as sensors for innate receptors
Nucleic acids can be potent triggers of innate immune responses 56, 57. Multiple transmembrane and cytosolic receptors have evolved to recognize RNA and DNA, including TLRs, retinoic-acid-inducible gene (RIG)-I-like receptors (RLRs) and several classes of DNA sensors. In particular, TLR3, TLR7, and TLR9 are present in endosomes where they sense double-stranded RNA (ds)RNA, single-stranded (ss)RNA and short dsRNA, and hypomethylated CpG-motif containing oligodeoxynucleotides (CpG ODNs),
HMGB proteins in cytosolic signaling pathways and antiviral responses
A critical role of HMGB proteins in cytosolic nucleic-acid-mediated activation of innate immune responses has been underscored by several experiments [66]. First, in mouse embryonic fibroblasts (MEFs) from HMGB1-deficient mice (Hmgb1−/− MEFs) the induction of mRNA for type I IFN, IL-6, and chemokine (C-C motif) ligand 5 (Ccl5) was significantly reduced when cells were cytosolically stimulated by poly(dA-dT)•poly(dT-dA) (referred to as B-DNA 62, 67) or poly(I:C). mRNA induction for these genes
HMGB proteins in nucleic-acid-mediated activation of TLRs
HMGB1 plays a role in the activation of all nucleic-acid-sensing TLRs, as demonstrated by poly(I:C)-TLR3, poly(U)-TLR7, and CpG-B ODN–TLR9 signaling 59, 66. In conventional DCs from Hmgb1−/− mice, the mRNA induction of proinflammatory cytokines upon stimulation of TLR3 by poly(I:C) or TLR9 by CpG-B ODN is impaired [66]. The induction of proinflammatory cytokine genes by these ligands is more severely impaired in HMGB-deficient RAW 264.7 cells, suggesting that other HMGBs or other genes also
Suppression of HMGB-mediated immune responses by nonimmunogenic nucleotides and its implications
Although the innate immune system can discriminate many self and non-self molecules, nucleic acids themselves are common to host and infectious microbes. Thus, recognition of self versus non-self nucleic acids by innate receptors must be in a delicate balance, and an imbalance of this system is closely linked to autoimmune and autoinflammatory disorders 75, 76. Indeed, ample evidence has been provided for the involvement of nucleic-acid-mediated immune responses in the animal models of
Therapeutic implications
Given the potent inflammatory functions and wide involvement in nucleic-acid-mediated immune responses, there has been much interest in inhibitors of HMGB1 activity for the treatment of inflammation-associated and other diseases. As a result, several such inhibitory molecules have been reported. For instance, anti-HMGB1 antibodies, when passively immunized, were found to protect significantly against lethal endotoxemia in mice in a dose-dependent manner [19]. In addition, specific HMGB1
Concluding remarks
HMGB1 is involved in many biologically important processes including transcription, DNA repair, differentiation, development, and extracellular signaling. The data discussed in this review underscore the fundamental role of the HMGB family of proteins in the regulation of immune responses as a ligand and a sensor. Thus, from the classical view of cellular biology, HMGB1 (and its family) is ostensibly an unusual protein because it shuttles from the nuclear to extracellular space, and performs
Acknowledgments
This work was supported in part by a Grant-In-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST).
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