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High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease.

Pisetsky DS, Erlandsson-Harris H, Andersson U - Arthritis Res. Ther. (2008)

Bottom Line: To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death.HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses.New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA. piset001@mc.duke.edu

ABSTRACT
High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 can serve as an alarmin to activate the innate system and mediate a wide range of physiological and pathological responses. To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death. HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses. As shown in studies on patients as well as animal models, HMGB1 can play an important role in the pathogenesis of rheumatic disease, including rheumatoid arthritis, systemic lupus erythematosus, and polymyositis among others. New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

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Related in: MedlinePlus

The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.
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Figure 1: The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.

Mentions: In this construct on the function of HMGB1, the important issue is not the contribution of any possible 'contamination' of purified HMGB1 in in vitro experiments but rather the actual function of the protein in vivo. We therefore would suggest that HMGB1 functions in vivo to enhance inflammation by binding PAMPs, DAMPs, and cytokines to promote dual-receptor interactions that may be especially effective because of their proximity. These receptors include RAGE, TLRs, β2-integrin Mac-1, and possibly others. HMGB1-dependent activation and recruitment of neutrophils have recently been described to require a functional interplay between Mac-1 and RAGE [26]. Thus, HMGB1 may act synergistically with other immunostimulatory molecules to modulate their interaction with cells and amplify their activity because of their physical association (Figure 1).


High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease.

Pisetsky DS, Erlandsson-Harris H, Andersson U - Arthritis Res. Ther. (2008)

The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483460&req=5

Figure 1: The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.
Mentions: In this construct on the function of HMGB1, the important issue is not the contribution of any possible 'contamination' of purified HMGB1 in in vitro experiments but rather the actual function of the protein in vivo. We therefore would suggest that HMGB1 functions in vivo to enhance inflammation by binding PAMPs, DAMPs, and cytokines to promote dual-receptor interactions that may be especially effective because of their proximity. These receptors include RAGE, TLRs, β2-integrin Mac-1, and possibly others. HMGB1-dependent activation and recruitment of neutrophils have recently been described to require a functional interplay between Mac-1 and RAGE [26]. Thus, HMGB1 may act synergistically with other immunostimulatory molecules to modulate their interaction with cells and amplify their activity because of their physical association (Figure 1).

Bottom Line: To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death.HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses.New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA. piset001@mc.duke.edu

ABSTRACT
High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 can serve as an alarmin to activate the innate system and mediate a wide range of physiological and pathological responses. To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death. HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses. As shown in studies on patients as well as animal models, HMGB1 can play an important role in the pathogenesis of rheumatic disease, including rheumatoid arthritis, systemic lupus erythematosus, and polymyositis among others. New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

Show MeSH
Related in: MedlinePlus