Front Immunol 11: 484

Targeting Inflammation Driven by HMGB1

HMGB1 Box A Protein

Recombinant HMGB1 box A protein has been successfully used to treat a number of experimental inflammatory models, but its mode of action has, until now, been an unresolved issue. The identification of box A-blockade of RAGE-mediated cellular import of HMGB1 and HMGB1-partner molecule complexes thus represents considerable progress, not the least because this knowledge enables an opportunity to evaluate the biological activity of individual box A batches in vitro. A lack of such technology has so far prevented a clinical development of box A protein. Beneficial preclinical effects by box A therapy was first reported in experimental arthritis (39), followed by CLP sepsis (35), transplantation (40), stroke (41), ischemia-reperfusion injury (42), pancreatitis (43), and acute lung injury (44).

Peptide P5779

Macrophages that do not express TLR4 do not display nuclear NF–κB translocation or cytokine production when activated by any HMGB1 redox isoform (7). Disulfide HMGB1 subjected to cysteine mutations or redox changes loses the ability to activate TLR4. MD-2 gene-deficient macrophages do not release TNF in response to disulfide HMGB1 or any other HMGB1 isoform. Disulfide HMGB1, like LPS, binds to MD-2 with low nanomolar avidity, but to distinct MD-2 epitopes. We generated a tetramer peptide (FSSE, designated P5779) as an HMGB1 inhibitor specifically targeting the HMGB1-TLR4/MD-2 pathway (9). P5779 binds exclusively to MD-2 at the HMGB1 binding site, which preserves the responsiveness to endotoxin. The P5779 peptide does not inhibit RAGE-mediated endocytosis of HMGB1 or HMGB1/LPS complexes. P5779 (but not the scrambled control peptide) dose-dependently inhibited HMGB1-induced TNF release without affecting LPS-induced cytokine and chemokine release in primary human macrophage cultures. Therapeutic administration of P5779 protected against experimental hepatic ischemia/reperfusion-induced injury, acetaminophen-induced liver toxicity and CLP sepsis lethality (9). Furthermore, the clinical outcome of murine influenza infection was significantly improved by treatment with P5779 (45). Therapy based on P5779 administration also alleviated experimental endoluminal arterial injury-induced intimal hyperplasia and up-regulation of TLR4, HMGB1, and IL-6 expression in the affected carotid vessels. Global TLR4 gene-deficient mice demonstrated reduced inflammation and diminished HMGB1 expression after arterial injury, further supporting that HMGB1 and TLR4 are essential for vascular inflammatory responses (46). P5779 treatment conferred a striking survival advantage in an experimental pulmonary arterial hypertension model (47). Using a molecular dynamic simulation approach and surface plasmon resonance analysis, Sun et al. (48) identified that several folic acid peptides mimic the binding interaction of P5779 at the TLR4/MD-2 interaction. Addition of these P5779 mimetic peptides inhibited HMGB1-induced TNF release in cultured human macrophages. Taken together, P5779 acts as an HMGB1- inhibitor specifically targeting HMGB1-TLR4 interaction and efficiently ameliorates HMGB1/TLR4-driven inflammatory diseases (Table 1; Figure 1).

Table 1

Summary of efficacy of P5779 in HMGB1-driven inflammatory diseases.

Models	Findings	References
Acetaminophen liver toxicity in mice	Improved survival, reduced serum liver enzymes, reduced liver necrosis	(9)
Liver ischemia/reperfusion in mice	Reduced serum liver enzymes and liver inflammation	(9)
CLP-sepsis in mice	Improved survival	(9)
Arterial injury model in mice	Reduced carotid artery injury-induced intimal hyperplasia and TLR4, HMGB1, and IL-6 expression in injured vessels	(46)
Influenza in nuce	Improved survival and reduced lung edema in influenza infection	(45)
Puhnonary hypertension in rats	Improved survival in monocrotaline-induced severe pulmonar y hypertension	(47)
In vitro	Reduced HMGB1-induced TNF release from cultured human macrophages	(48)

Anti-HMGB1 mAb (m2G7)

Since the development of our anti-HMGB1 m2G7 (34), many laboratories have independently confirmed the efficacy of other anti-HMGB1 mAb in many different models of sterile or infectious inflammation. The m2G7 binds to an epitope in the box A (located in HMGB1 sequence amino acids 53–63) and this binding functionally affects both HMGB1 interactions with RAGE and TLR4. Other published anti-HMGB1 mAbs have not been studied from the perspective of HMGB1 receptor inhibition and thus will not be further discussed in this section.

The m2G7 has been demonstrated to inhibit TNF production in macrophages activated by recombinant disulfide HMGB1, by HMGB1 from cultured HMGB1-transfected mammalian cells, and by HMGB1 derived from necrotic fibroblasts (7, 9). This is proof of m2G7-caused antagonistic effects on HMGB1-TLR4-mediated processes. There are many examples of preclinical HMGB1-dependent models which respond favorably to therapeutic administration of the m2G7 (Table 2). However, the inflammation is generally caused by HMGB1 activation of both TLR4 and RAGE and it is most often not possible to discriminate between the specific contributions by each receptor system. The first evidence of successful performance by the m2G7 in vivo came from CLP sepsis studies (34), when m2G7 therapy improved survival, a result which was confirmed in the recent report by Deng et al. (11). Systemic HMGB1 levels are increased during the acute stage of sepsis, but persistently elevated for weeks or months in both mice and patients for unknown reasons (50, 56–58). The increased HMGB1 levels post-sepsis exert a causative role for post-sepsis complications including cognitive dysfunction and anemia in the mouse CLP model. Both complications also occur after clinical sepsis, but the molecular background for this is unresolved. It is tempting to suggest HMGB1 as a cause also in the clinical situation, since HMGB1 is 99% identical in all mammals. Mice surviving CLP sepsis developed significant and persistent impairment in learning and memory, and anatomic changes in the hippocampus. Administration of the m2G7 10 days from the onset of CLP-sepsis to the survivors significantly ameliorated memory and learning disabilities, and hippocampal pathology. Systemic administration of disulfide HMGB1 reproduced the neuropathology seen after CLP sepsis (49). Systemic HMGB1 administration also caused anemia with extramedullary erythropoiesis just like CLP surviving mice. Treatment with the m2G7, provided post the acute CLP-sepsis stage, prevented the development of anemia in sepsis survivors in mice (50).

Table 2

Summary of efficacy of anti-HMGB1 m2G7 in HMGB1-driven inflammatory diseases.

Models/species	Findings	References
Infectious diseases
CLP sepsis or endotoxemia in mice	Reduced lethalit y in CLP-induced sepsis and in endotoxemia	(11, 34)
CLP sepsis-survivors in mice	Reduced sepsis-induced memory impairments and brain pathology in survivors	(49)
CLP sepsis-survivors in mice	Ameliorated sepsis-induced development of anemia and stress erythropoiesis	(49, 50)
Sterile injury
Islet transplantation in diabetic mice	Improved islet viability and reduced transplantation-induced inflammation	(51)
Chronic arthritis in mice	Ameliorated clinical arthritis scores, partially prevented joint destruction	(52)
Arthritis pain in mice	Ameliorated pain-like behavior in collagen antibody induced arthritis	(53)
Acetaminophen (APAP)-induced liver toxicity in mice	Attenuated APAP-induced release of ALT, microRNA-122, and abrogated inflammation	(9, 54)
Autoimmune myocarditis in mice	Reduced cardiac inflammation	(55)
Puhnonary hypertension in rats	Improved survival in monocrotaline-induced severe puhnonary hypertension	(47)

Multiple preclinical inflammatory sterile injury models likewise respond positively to m2G7 therapy. Improved islet viability and reduced inflammation after syngeneic islet graft transplantation in diabetic mice were observed in response to systemic m2G7 therapy (51). Collagen-induced arthritis and a spontaneous arthritis model were both ameliorated by m2G7 treatment. Joint destruction was prevented and clinical arthritis scores improved (52). Intrathecal m2G7 injection reversed collagen antibody-induced arthritis-induced chronic pain reactions (53). HMGB1 is an important down-stream mediator in the pathogenesis of acetaminophen intoxication and causes serious liver damage. Treatment with m2G7 significantly inhibited acetaminophen-induced release of hepatic enzymes, pro-inflammatory cytokines, and improved survival in mouse studies (9). Lundback et al. (54) confirmed these experimental results and demonstrated that administration of a humanized version of the m2G7 significantly attenuated acetaminophen-induced elevation of microRNA-122, a liver-specific microRNA, and serum levels of TNF, MCP-1, and CXCL1. Likewise, survival in experimental pulmonary hypertension in rats was significantly enhanced after m2G7 treatment (47). Systemic, as well as cardiac, HMGB1 levels are increased in mice with troponin-induced experimental autoimmune myocarditis and m2G7-based therapy reduced the cardiac inflammation and HMGB1 expression (55) (Table 2).

There are also reported therapeutic failures with the m2G7 in preclinical trials. Administration of m2G7 in a mouse model of amyotrophic lateral sclerosis showed overall very limited efficacy (59).

Treatment with m2G7 did not affect lupus nephritis in MRL/lpr mice, despite the fact that systemic levels of HMGB1 are increased in lupus (60). Successful therapeutic outcome has in contrast been reported in another mouse lupus model using a different anti-HMGB1 mAb (61).

Resveratrol

Resveratrol is a phytoalexin phenol molecule acting as a protective endogenous antibiotic when produced in plants under stress. Resveratrol also reduces LPS-induced levels of HMGB1, IL-6, NO, and TNF in RAW 264.7 cell cultures. This TLR4-dependent process was downregulated by resveratrol-mediated inhibition of TLR4 expression (62). Resveratrol, markedly inhibited microglia activation and display of TLR4, HMGB1, MyD88, and NF-κB in the brain cortex in an experimental subarachnoid hemorrhage model (63). Furthermore, resveratrol demonstrated similar neuroprotective and anti-inflammatory effects in a neonatal hypoxic-ischemic brain injury model. Mechanistic in vitro and in vivo studies indicated that resveratrol activated SIRT1 to reduce HMGB1/TLR4/MyD88/NF-κB signaling and subsequent neuroinflammatory responses (64). The compound also demonstrated beneficial effects in an asthma model by decreasing the expression of HMGB1, TLR4, MyD88, and NF-κB mRNA levels in the lung tissue and significantly decreased the thicknesses of the airway walls (65). Together, these results indicate that resveratrol ameliorates inflammation in part via inhibition of HMGB1/TLR4-mediated inflammation (Figure 1).

Dexmedetomidine

Dexmedetomidine is a α2-adrenoceptor agonist with anti-inflammatory effects mediated via activation of the cholinergic anti-inflammatory pathway (66). Dexmedetomidine treatment in experimental endotoxemia attenuated inflammation through downregulated TLR4 expression via a α7 nicotinic acetylcholine receptor-dependent pathway (67). It is thus of great interest that acetylcholine has the capacity to functionally inhibit both the TLR4 and RAGE pathways, the major receptor HMGB1 systems (32, 67, 68).

Anti-HMGB1 mAb #10–22

Another extensively studied anti-HMGB1 mAb has been developed by a Japanese research group (69). The antibody, termed #10–22, recognizes an epitope in the repetitive C-terminal sequence. Successful therapeutic interventions are reported in a number of experimental neuro-inflammatory conditions, including stroke (70), traumatic brain injury (71), cognitive dysfunction after traumatic brain injury (72), spinal cord injury (73), epilepsy (74, 75), blood brain barrier dysfunction after CNS ischemia (76), hemorrhage-induced brain injury (77), neuropathic pain (78–83), and neuropathic pain-related depressive behavior (84). The antibody has also demonstrated beneficial effects in severe mouse influenza models (85, 86). Taken together, these findings demonstrated impressive treatment results in severe preclinical disease models.

Thrombomodulin

Thrombomodulin is an endothelial cell thrombin receptor that converts thrombin into an anticoagulant. Soluble thrombomodulin also binds to HMGB1 and aids the proteolytic cleavage of HMGB1 by thrombin (87). Recombinant thrombomodulin is successfully used in Japan to treat patients with disseminated intravascular coagulation in sepsis (88).

Haptoglobin

The major task of the acute phase protein haptoglobin is to bind and eliminate extracellular hemoglobin. Haptoglobin is in addition capable of capturing extracellular HMGB1. The haptoglobin-HMGB1 binds to CD163 on macrophages activating an anti-inflammatory response mediated via IL-10 and heme-oxygenase 1 production (89). Therapeutic administration of haptoglobin improved septic shock, lung injury, and survival in a canine pneumonia model (90). Haptoglobin is approved as an adjuvant therapy for patients in Japan with trauma, burns, and transfusion-related hemolysis.

Metformin

Metformin occupies an important role in type 2 diabetes treatment. Metformin also has an anti-inflammatory effects, although these effects are not mechanistically fully understood. Metformin inhibits nuclear HMGB1 translocation to the cytosol and thus retains HMGB1 in the nucleus after cell activation (91). Metformin also binds directly to the C-terminal domain of HMGB1 and down-regulates inflammation by counteracting the extracellular activity of HMGB1 (92). Furthermore, the compound inhibits HMGB1 release and increases survival rate of endotoxemic mice (93).

DNA-Conjugated Beads

HMGB1 is released and present at high levels in intestinal tissue and feces in patients with chronic inflammatory bowel diseases (IBD). Several experimental IBD models have responded very well to systemic treatment with neutralizing anti-HMGB1 antibodies. HMGB1 is a well-known DNA-binding protein, which offers an opportunity to sequester HMGB1 via DNA-conjugated beads that has been studied in experimental colitis. Oral treatment with DNA-conjugated beads significantly improved outcome in two different preclinical colitis models (94).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^{Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, United States}

^{Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, United States}

^{Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden}

Edited by: Jeon-Soo Shin, Yonsei University, South Korea

Reviewed by: Masahiro Nishibori, Okayama University Graduate School of Medicine, Japan; Melanie J. Scott, University of Pittsburgh, United States

*Correspondence: Huan Yang ude.llewhtron@gnayh

Ulf Andersson es.ik@nossredna.flu

This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

Edited by: Jeon-Soo Shin, Yonsei University, South Korea

Reviewed by: Masahiro Nishibori, Okayama University Graduate School of Medicine, Japan; Melanie J. Scott, University of Pittsburgh, United States

Received 2020 Jan 14; Accepted 2020 Mar 2.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.

Keywords: HMGB1, inflammation, danger signal, RAGE, TLR4, drug target

Abstract

Footnotes

Funding. This project was supported in part by grants from the NIH, NIGMS, 1R35GM118182 (to HY), R01GM063075 (to HW) and the National Center of Complementary and Integrative Health (NCCIH), R01AT005076 (to HW). Torsten Soderberg's foundation (to UA).

Footnotes

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