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. 2021 Nov 19;43(1):47–58. doi: 10.1007/s10571-021-01170-8

HMGB1 is a Potential and Challenging Therapeutic Target for Parkinson’s Disease

Yu Tian 1,2, Rong Chen 1,2, Zhaoliang Su 1,2,✉
PMCID: PMC11415213  PMID: 34797463

Abstract

Parkinson’s disease (PD) is one of the most common degenerative diseases of the human nervous system and has a wide range of serious impacts on human health and quality of life. Recently, research targeting high mobility group box 1 (HMGB1) in PD has emerged, and a variety of laboratory methods for inhibiting HMGB1 have achieved good results to a certain extent. However, given that HMGB1 undergoes a variety of intracellular modifications and three different forms of extracellular redox, the possible roles of these forms in PD are likely to be different. General inhibition of all forms of HMGB1 is obviously not ideal and has become one of the biggest obstacles in the clinical application of targeting HMGB1. In this review, pure mechanistic research of HMGB1 and in vivo research targeting HMGB1 were combined, the effects of HMGB1 on neurons and immune cell responses in PD are discussed in detail, and the problems that need to be focused on in the future are addressed.

Keywords: HMGB1, Parkinson’s disease, Autophagy, Neuroinflammation, T cell, Microglia

Introduction

Parkinson’s disease (PD) is a common central nervous system disease, with more than 6 million patients worldwide, and in the past decade, the global increase in PD has been particularly rapid, while the reason behind it is not clear (Collaborators 2019). Although PD has typical symptoms such as tremor and slowed movement, the clinical manifestations of different patients vary, which may be related to the diversity of causes of PD (Armstrong and Okun 2020). The causes of PD include neurotoxins and environmental toxins, genetic mutations and their interaction (Trinh et al. 2018; Nonnekes et al. 2018). It is difficult to cure PD because of these diverse clinical manifestations and pathogenic factors. However, all PD is pathologically caused by a decrease in dopaminergic neurons in the SN. Abnormal deposition of α-synuclein and long-term chronic neuritis are also found in PD patients and different animal models (Williams et al. 2021; Depboylu et al. 2012).

Recently, the proinflammatory effect of extracellular high mobility group box 1 (HMGB1) in PD has been reported, and a number of HMGB1 blockade studies on animal models of PD have produced positive results (Nishibori et al. 2019; Yang et al. 2018; Tian et al. 2020). However, there has been little progress in the clinical application of blocking HMGB1, and the role of HMGB1 in PD does not seem simple. HMGB1 is a nonhistone protein that is widely present in the nucleus in eukaryotes. HMGB1 plays an important role in stabilizing DNA and regulating transcription (Pellegrini et al. 2019; Kohlstaedt et al. 1987). HMGB1 is highly evolutionarily conserved, and both human and murine HMGB1 are composed of 215 amino acids. HMGB1 consists of an A box (aa9-79), a B box (aa95-163) and an acidic C-terminus (aa179-185) (Yang et al. 2015a; Richard et al. 2017). The B box retains the proinflammatory properties of HMGB1, while the A box antagonizes the proinflammatory properties of HMGB1 (Li et al. 2003; Yang et al. 2004; Tian et al. 2020).

HMGB1 has three cysteine sites (C23, C45 and C106), and the different redox states of these three sites determine the different functions of HMGB1 (Lu et al. 2014; Wu et al. 2015a; Hoppe et al. 2006; Urbonaviciute et al. 2009). When the sulfhydryl groups at these three sites of HMGB1 are fully reduced (frHMGB1), this protein does not promote inflammation. The negative reduction potential of the cytoplasm and nucleus maintain the reduction state of HMGB1 (Hoppe et al. 2006). However, the sulfhydryl groups at the three cysteine sites of HMGB1 are not stable in vitro (Kohlstaedt et al. 1986). The half-life of frHMGB1 in human serum and saliva is only 17 min (Zandarashvili et al. 2013). The relatively high level of extracellular oxide can form disulfide bonds between the two cysteine sites at C23 and C45, forming disulfide HMGB1 (dsHMGB1), which has proinflammatory effects (Zhang et al. 2015). In tissue injury or inflammation, ROS released by inflammatory cells may further reduce the presence of frHMGB1 (Venereau et al. 2012; Dumitriu et al. 2007). dsHMGB1 is a DAMP that binds with TLRs and receptor for advanced glycation end products (RAGE) and causes the activation of NF-κB, which leads to the release of inflammatory factors and chemokines (Park et al. 2004; Huttunen et al. 1999). This process is similar to that of LPS, but the effect of dsHMGB1 is very limited and less robust than that of LPS (Yang et al. 2015b, 2010). However, frHMGB1 released by injured cells, which forms dsHMGB1 in the extracellular environment, and dsHMGB1 released by inflammatory cells play important roles in maintaining inflammation (Aucott et al. 2018). The high ROS environment at the injured site oxidizes the disulfide bond and sulfhydryl group of dsHMGB1 to a sulfonic group, which transforms the three cysteine sites of dsHMGB1 into sulfonates and inactivates dsHMGB1 into sulfonyl HMGB1 (fully oxidized HMGB1) (Venereau et al. 2013; Palmblad et al. 2015) (Fig. 1). However, during PD, neuronal death to glial cell activation, the destruction of the blood–brain barrier (BBB) and the entry of peripheral immune cells occur, the origin of HMGB1 is difficult to trace, and the function of intracellular HMGB1 is hard to determine. It is believed that HMGB1 has different roles in different cell types.

Fig. 1.

Fig. 1

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Structure and function of HMGB1. a Structure of a complex of HMGB1 and DNA. b Three-dimensional structure of the HMGB1 protein. c Primary structure and binding site of HMGB1. d Three different redox forms of extracellular HMGB1

HMGB1 is modified in different ways, such as phosphorylation, acetylation and methylation, and has different forms. At present, the differences between these different modified forms and their roles are not very clear (He et al. 2015). Glycyrrhizin and ethyl pyruvate (EP), which are HMGB1 inhibitors with multiple effects, have side effects. Whether these agents affect the transcription, translation and modification of HMGB1 in cells is unclear due to a lack of laboratory evidence. There are potential concerns about their long-term application in PD patients as drugs targeting HMGB1. It is particularly important to profile HMGB1 accurately and completely.

Roles of Intracellular HMGB1 in Neurons

Although the positive effect of extracellular HMGB1 on inflammation is widely known, the role of intracellular HMGB1 is very different. In the nucleus, HMGB1 loosely binds to chromosomes and maintains the stability of genetic material, including telomere DNA (Mandke and Vasquez 2019; Mitsouras et al. 2002; Park et al. 2003). During aging, the level of HMGB1 in the serum and neuronal nuclei of healthy individuals gradually decreases, accompanied by the accumulation of DNA double strand breaks (Fu et al. 2016; Qi et al. 2007; Enokido et al. 2008). In PD caused by simple aging without the accumulation of neurotoxic substances, the mechanism of early neuronal degeneration may be closely related to this phenomenon (Hou et al. 2019). However, there is still insufficient evidence to explain why aging-related DNA double strand breaks occur preferentially in dopaminergic neurons (Milanese et al. 2018; Flones et al. 2018). In addition, HMGB1 knockdown induced a significant decrease in telomerase activity and telomere DNA damage in mouse embryonic fibroblasts and HeLa cells (Polanska et al. 2012). Overexpression of HMGB1 enhanced telomerase activity, which suggests that the decrease in HMGB1 in the nucleus may be closely related to senescence and death in dopaminergic neurons (Polanska et al. 2012; Amato et al. 2019; Jaskelioff et al. 2011).

The translocation of HMGB1 from the nucleus to the cytoplasm leads to the dissociation of Beclin1-Bcl-2 by HMGB1 binding to Beclin1 and induces autophagy, which promotes the self-clearance of α-synuclein (α-syn) (Tang et al. 2010). Furthermore, the abnormal accumulation of α-syn leads to persistent inflammation and neurodegeneration (Harms et al. 2013, 2018; Giasson et al. 2000). Experiments on the PC12 cell line confirmed that inhibiting HMGB1 translocation led to the accumulation of α-syn and exacerbated neuronal damage due to a lack of autophagy (Fig. 2) (Wang et al. 2016; Song et al. 2014; Han et al. 2019). Additionally, with the decrease in HMGB1 in aging neurons, Beclin1-Bcl-2 is not sufficiently dissociated, and autophagic clearance of α-syn is weakened, which may cause the accumulation of α-syn (Lindersson et al. 2004).

Fig. 2.

Fig. 2

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Interaction between intracellular HMGB1 and dopaminergic neurons. Aging or other factors lead to a decrease in HMGB1 in the nucleus in dopaminergic neurons, an increase in DNA instability, including that of telomere DNA, more DNA double strand breaks, and other DNA damage, and eventually lead to aging and death in neurons. The combination of α-syn accumulation in PD and HMGB1 in the nucleus hinders its nucleation. The binding of α-syn to HMGB1 inhibits the binding of HMGB1 to Beclin1, which can relieve the autophagy inhibition induced by Beclin1/Bcl-2. α-Syn ultimately impairs the autophagic clearance of itself by binding to intracellular HMGB1

How Extracellular HMGB1 Affects the Progression of PD

Increased HMGB1 was detected in the serum and cerebrospinal fluid of PD patients and the SN of PD model animals, and the upregulation of TLRs, RAGE and other receptors downstream of HMGB1 also confirmed that extracellular HMGB1 may play an important role in PD (Yang et al. 2018; Lv et al. 2019). In PD, the increase in HMGB1 is not as significant as that in trauma or acute inflammation. However, in animal models of PD, the loss of dopaminergic neurons was inhibited by glycyrrhizin and ethyl pyruvate, which inhibit HMGB1, or HMGB1 neutralizing antibodies. dsHMGB1 binds TLR4 and activates the NF-κB pathway in immune cells and promotes the inflammatory response. This effect is similar to but far weaker than that of LPS (Yang et al. 2010). In a model of peripheral organ injury, frHMGB1 recruited monocytes/macrophages to infiltrate the injury site (Schiraldi et al. 2012; Tirone et al. 2018). The BBB separates the central nervous system (CNS) and the peripheral blood circulation, and there are a large number of microglia in the CNS with the advantages of location and quantity in PD patients and animal models. However, the downregulation of CD200R and the infiltration of macrophages in the SN in model mice were observed (Luo et al. 2010). BBB function is impaired in animal models and patients with PD, which is the pathological basis of peripheral immune cell infiltration into the substantia nigra (SN) (Shaltiel-Karyo et al. 2013; Janelidze et al. 2015; Sweeney et al. 2018). Therefore, how HMGB1 recruits peripheral immune cells in CNS diseases is particularly interesting. In PD model mice and PD patients, HMGB1, which should be limited intracellularly, appeared in the cytoplasm of TH+ neurons, microglia and astrocytes in the SN, which indicated that many cells were in a stressed state and released or secreted HMGB1 to play a corresponding role in the pathogenesis of PD (Santoro et al. 2016).

frHMGB1

When tissue cells are damaged, frHMGB1 is released after the cells disintegrate. frHMGB1 has no ability to recruit immune cells, but frHMGB1 forms a complex with CXCL12 in tissues, which specifically binds to CXCR4 on the surface of other cells to mediate cell migration (Schiraldi et al. 2012). Most CXCR4-expressing cells migrate in response to frHMGB1/CXCL12 (De Leo et al. 2019; Zhao et al. 2020). frHMGB1 enhanced the ability of CXCL12 to induce cell migration by at least 12-fold (Schiraldi et al. 2012; Venereau et al. 2012). In the CNS, microglia are the main immune cells and are first exposed to harmful factors. In the SN tissue of PD patients, increased α-synuclein and CXCL12 are positively correlated with CXCR4 in microglia (Li et al. 2019). Therefore, microglia may migrate and activate frHMGB1/CXCL12 in vivo. The activation of microglia and the increased expression of MHC II on the surface of microglia, including those in PD, suggest that microglia may be antigen-presenting cells (Li et al. 2019; Imamura et al. 2003; Das and Chinnathambi 2019; Wolf et al. 2018). However, in the EAE model, there was no significant difference in disease severity between microglia-specific MHC II-deficient mice and normal mice, and in a coculture system of pure microglia and midbrain cells without other peripheral immune cells, the proportion of Th17+ cells induced by microglia in the MPP+ environment was significantly lower than that in the in vivo MPTP model with peripheral cells. Many signs suggest that microglia may not be the only or main antigen-presenting cells (Wolf et al. 2018; Wlodarczyk et al. 2014; Tian et al. 2020).

In the past, due to the existence of the BBB, macrophages and dendritic cells (DCs) could not enter the brain, and few studies have focused on their roles in PD. Recently, some studies have shown that CCR2+ peripheral monocytes strongly infiltrate the SN in response to the overexpression of human α-syn and that knockout of CCR2 significantly reduces the loss of TH+ neurons (Harms et al. 2018). Increased monocytes and higher levels of CCL2 were also detected in the peripheral blood of patients with PD (Grozdanov et al. 2014). Interestingly, CCR2+ DCs and CXCR4+ monocytes/macrophages can migrate in response to CCL2 and the frHMGB1/CXCL12 complex in vitro, and in experimental autoimmune cerebrospinal meningitis, CCR2+ DCs infiltrated the CNS and promoted the infiltration and activation of effector T cells and disease progression, which indicates that both DCs and monocytes/macrophages have the ability to infiltrate the CNS (Campana et al. 2009; Clarkson et al. 2015). However, there have been few reports on the contribution of DCs to PD. Based on the characteristics of peripheral mononuclear macrophages and DCs, these cells may migrate into the CNS in response to the formation of the frHMGB1/CXCL12 complex after injury to neurons in PD.

Increased levels of HMGB1, CXCL12 and CXCR4 in cerebrospinal fluid or serum were detected in PD patients and mouse models (Bagheri et al. 2018; Shimoji et al. 2009; Santoro et al. 2016; Pashenkov et al. 2003). This mechanism of frHMGB1 may play an important role in the course of PD. In response to the frHMGB1/CXCL12 complex, antigen-presenting cells that migrate to damaged neurons, including microglia, macrophages and DCs, may be closely related to the chemotaxis, infiltration and activation of peripheral T cells in the SN.

dsHMGB1

The frHMGB1 released by injured neurons becomes dsHMGB1 under the influence of high levels of ROS and other oxidants produced by activated inflammatory cells. Unlike frHMGB1, dsHMGB1 could not bind CXCL12 but could bind to TLRs on glial cells, activate downstream NF-κB and induce the production of various inflammatory mediators (Venereau et al. 2012; Yang et al. 2015b, 2010). Rosiszewski et al. demonstrated that in astrocytes, NF-κB was activated by the response of TLRs to dsHMGB1 in vitro, which depends on the presence of microglia, and the simultaneous existence of microglia and astrocytes enables HMGB1 to induce hippocampal neuron degeneration (Rosciszewski et al. 2019).

The expression of TLRs was upregulated in PD patients and animal models, which also confirmed the role of dsHMGB1 (Yang et al. 2018; Lv et al. 2019; Teismann et al. 2012). Elevated TNF-α may directly and indirectly cause neuronal death (Fritze et al. 2014; Kaur et al. 2014; Ding et al. 2016; Kraft et al. 2009; Wang et al. 2005). A previous study confirmed that the levels of IL-1β, IL-6, TNF-α and CXCL12 in the SN of MPTP model mice were significantly decreased after using HMGB1 A Box recombinant protein to competitively inhibit dsHMGB1 in vivo. The production of IL-1β was also induced by intracerebral injection of dsHMGB1 (Tian et al. 2020; Aucott et al. 2018). Astrocyte activation in PD was previously confirmed, and the upregulation of IL-1β may induce astrocytes to increase production of CXCL12 through the ERK and PI3K signaling pathways (Sasaki et al. 2016; Calderon et al. 2006; Peng et al. 2006). Over time in PD, dopaminergic neurons continue to release new frHMGB1, which may maintain a certain level of the frHMGB1/CXCL12 complex in the CNS and stimulate the migration of peripheral immune cells to the CNS (Fig. 3). Additionally, HMGB1 has been reported to be involved in the regulation of microglial activation and neuronal apoptosis (Cheng et al. 2020). In diabetic patients, the interaction of dsHMGB1 and TLR4 inhibited autophagy and promoted apoptosis in hippocampal neurons (Guo et al. 2019). However, primary neurons lack TLR4, and so dsHMGB1 may indirectly affect neuronal autophagy by affecting TLR4-expressing immune cells in the nervous system.

Fig. 3.

Fig. 3

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Interaction between extracellular HMGB1 and immune cell response patterns in PD. The frHMGB1/CXCL12 complex formed by frHMGB1 that was released from damaged dopaminergic neurons and CXCL12 at basic concentrations in the healthy midbrain, which greatly enhanced the chemotactic activity of CXCL12 to immune cells. Microglia around damaged neurons migrate to the damaged site and are activated. In response to CXCL12-induced chemotaxis, peripherally derived macrophages or DCs enter the midbrain through the damaged BBB and are activated. The activated immune cells in the midbrain actively secrete dsHMGB1 and IL-1β to exacerbate the inflammatory response and continuously stimulate astrocytes to secrete more CXCL12. Chemokines such as CCL5 (RANTES) produced in the inflammatory environment induce T cell migration, while microglia and infiltrating peripheral immune cells present antigens to T cells and promote T cell differentiation

Sulfonyl HMGB1

FrHMGB1 is completely oxidized to sulfonyl HMGB1 in a high ROS environment and then degraded. Since the three cysteine sites of sulfonyl HMGB1 are completely replaced by sulfonic groups, this form has no significant chemotactic or proinflammatory activities (Venereau et al. 2013).

Current Laboratory Methods to Target HMGB1 in PD

Given that CNS regeneration is virtually impossible, treatment for dopaminergic neuron regeneration or replacement remains unclear (Qian et al. 2020). Currently, for PD patients with dyskinesia, some specific physical therapy strategies are used to enhance the exercise ability, and using the patient’s own exercise ability and alternative exercise methods can bypass the defective ganglion circuit and achieve a certain degree of improvement in exercise ability (Nonnekes et al. 2019). However, specialized physical training cannot completely alleviate the symptoms of movement disorders in PD patients, and their quality of life still needs more improvement (Ypinga et al. 2018). The loss of dopaminergic neurons in PD patients leads to a significant decrease in dopamine levels in the striatum. Levodopa is widely used and can supplement dopamine and significantly improve disease-related movement disorders. However, long-term use of levodopa may cause many adverse reactions, including levodopa-induced dyskinesia (Subramaniam et al. 2011). At present, the methods that are routinely used in the clinical treatment of PD are very limited. It is important to find a universal, long-term, stable, and safe treatment strategy.

HMGB1 neutralizing antibodies or inhibitors showed good effects in models of liver injury, autoimmune encephalitis and other inflammatory or traumatic diseases (Wang et al. 2014; Robinson et al. 2013; De Leo et al. 2019; Wu et al. 2015b; Musumeci et al. 2014). Since a negative effect of HMGB1 in PD has been found, research on inhibiting HMGB1 to treat PD is ongoing. Sasaki t et al. used an HMGB1 monoclonal antibody to improve the loss of dopaminergic neurons and PD behavioral symptoms in a 6-OHDA-induced PD rat model (Sasaki et al. 2016). Santoro M et al. used the biological small molecule glycyrrhizin to significantly preserve the number of TH+ neurons in the SN and reduce the levels of HMGB1 and RAGE in an MPTP-induced subacute PD model in mice. However, in this study, the protein levels of HMGB1 and RAGE in the SN were not compared to those of a normal mouse control group; thus, the extent to which glycyrrhizin inhibits HMGB1 remains to be determined (Santoro et al. 2016). Glycyrrhizin can resist ROS damage, and oxidative damage is one of the pathogenic processes in PD; therefore, glycyrrhizin should protect TH+ neurons (Wang et al. 2011; Musgrove et al. 2019). EP has a similar inhibitory effect on HMGB1 as glycyrrhizin, a common ester compound, and EP has a clear inhibitory effect on HMGB1 in disease models of myocardial ischemia–reperfusion, colitis and dust-induced airway inflammation (Soh et al. 2018; Bhat et al. 2019; Dave et al. 2009). EP may inhibit the phosphorylation and subsequent release of HMGB1 by chelating intracellular Ca2+ (Shin et al. 2015). Seo MS et al. demonstrated in a renal ischemia–reperfusion model that the effect of EP on reducing plasma HMGB1 was abolished by a heme oxygenase-1 inhibitor (Seo et al. 2019). The use of EP to treat PD also achieved good results in the restoration of TH+ neurons and improving motor disorders in model animals, but these studies only focused on the antioxidant effect of EP and did not examine the inhibitory effect of EP on HMGB1 (Huh et al. 2011; Satpute et al. 2013; Haga et al. 2019). It is less clear to what extent drugs with multiple effects play protective roles by inhibiting HMGB1. Recently, HMGB1 A box recombinant protein was applied in a PD mouse model and exerted considerable anti-inflammatory effects. Compared with that of EP, a lower dose of A box had a better anti-inflammatory effect, especially in inhibiting T cell-mediated inflammation (Tian et al. 2020). Due to the characteristics of HMGB1 A Box, the inhibition of HMGB1 has indisputable specificity. Because HMGB1 A box is less well studied than other HMGB1 inhibitors, further research may be necessary to more accurately target HMGB1.

Limitations of Laboratory Methods to Target HMGB1

Side Effects

Although the use of HMGB1 monoclonal antibodies and bioactive molecules, including glycyrrhizin and EP, which inhibit HMGB1, showed good neuroprotective effects in a PD model in mice or rats, due to the side effects of monoclonal antibodies, such as hematological diseases and autoimmune diseases, the long-term safety of using antibodies in the human body is limited (Sasaki et al. 2016; Santoro et al. 2016; Huh et al. 2011; Kim et al. 2016; Hansel et al. 2010). For glycyrrhizin, some adverse side effects have been reported (Nazari et al. 2017). EP, a nonspecific HMGB1 inhibitor, only inhibited the release of HMGB1 from living cells but not from dead cells (Kim et al. 2016; Seo et al. 2019). P5779 specifically inhibits the binding of HMGB1-TLR4/MD2 without affecting the binding of TLRs to other ligands (Yang et al. 2015b).

Obstacles in Selecting the Appropriate Timing for Inhibitor Application

The existing laboratory methods for HMGB1 inhibition are all aimed at counteracting the proinflammatory effect of HMGB1. In the early stage of PD, there is less significant inflammatory damage, and it is hard to evaluate the level and type of inflammation in the SN of PD patients. Whether these laboratory methods can be applied to all PD patients needs more rigorous examination.

In the PD model, neutralizing antibodies or other HMGB1 inhibitors inhibited microglial activation and T cell infiltration and restored the number of dopaminergic neurons. However, it is still unclear whether blocking HMGB1 in PD will inhibit the infiltration of monocytes/macrophages, even though some other disease models and in vitro experiments confirmed that inhibiting HMGB1 effectively inhibited the migration and infiltration of monocytes/macrophages into the injured site. This topic requires further research to understand the pathophysiological changes after inhibiting HMGB1 in PD.

The Difficulty in Distinguishing Between ‘Good’ and ‘Bad’ HMGB1

Studies have shown differences in the effect of astrocyte-derived HMGB1 on neurons. In contrast to the conclusions of many other studies on PD, Kim SJ et al. recently injected recombinant HMGB1 protein into the striatum in an acute MPTP mouse model, and the loss of TH was inhibited. This process depends on the participation of JNK and RAGE and is related to HMGB1-mediated promotion of TH transcription (Kim et al. 2019). According to the immunofluorescence results, most HMGB1 in the MPTP model came from astrocytes. This finding contradicts that of a previous study, which observed significantly increased translocation of HMGB1 from the nucleus to the cytoplasm in neurons, microglia and astrocytes in the SN of an MPTP mouse model (Santoro et al. 2016). Rosiszewski et al. showed that astrocytes are necessary for HMGB1-mediated neuronal injury, which also seems to contradict the findings of Kim SJ et al. (Rosciszewski et al. 2019).

In addition, intracellular HMGB1 is closely related to protein transcription, translation, and modification, cell aging, apoptosis, mutation and other cell activities (Amato et al. 2019; Ghaffari et al. 2021; Sofiadis et al. 2021; Liu et al. 2014). As the oldest evolutionarily conserved protein, HMGB1 has very complex forms and functions. There is no way to determine the potential effects of long-term use of some existing strategies to inhibit HMGB1 inside normal cells. In addition, intracellular HMGB1 is closely related to neuronal autophagy in PD. The accumulation of α-syn was related to the nucleocytoplasmic translocation of HMGB1. The binding of α-syn and HMGB1 further inhibited the autophagic clearance of α-syn by neurons, and the accumulation of α-syn continued to cause CNS inflammation. All the existing evidence suggests that it may not be appropriate to inhibit HMGB1 and focus instead on reducing the level of HMGB1, and determining ways maintain the normal level and state of HMGB1 inside of cells. Thus, HMGB1 antagonists that influence HMGB1 synthesis or binding with DNA should be applied cautiously.

More Unanswered Questions

Higher levels of HMGB1, TLR2, TLR4 and RAGE were detected in PD patients and animal models, indicating that HMGB1 and the signaling pathways downstream of these three receptors play roles in PD (Dzamko et al. 2017; Zhang et al. 2013). The binding of HMGB1 to these receptors has long been considered to promote the progression of inflammation, and their interaction promotes the development of chronic neuroinflammation. Recent evidence has shown that the binding of HMGB1 and RAGE promotes the expression of TH (Kim et al. 2019, 2017). TLR4 activation was shown to promote not only inflammation but also the clearance of α-synuclein, which has a positive effect on the treatment of PD (Venezia et al. 2017). The emergence of this new evidence makes inhibiting HMGB1 and its three receptors less accurate than we previously thought. Given that the timecourse of the PD animal model is short compared with the course of PD in humans, it seems unclear whether the current laboratory methods of inhibiting HMGB1 will lead to poor outcomes after long-term application.

How much HMGB1 affects the pathological process of PD is still unclear. Whether changes in HMGB1 occur before or after SN inflammation remains unclear. There are indications that the level of HMGB1 in neurons gradually decreases with aging, but why dopaminergic neurons in PD patients are more vulnerable to damage is still hard to answer. Moreover, HMGB1 has different posttranslational modifications in different cells, such as acetylation, phosphorylation, methylation, glycosylation and ubiquitination. These modifications closely affect the nucleocytoplasmic translocation of HMGB1. In PD, whether HMGB1 in different cells in the SN, has different posttranslational modifications or whether HMGB1 synthesized and released by different cells affects the function of cells in different ways and participates in the progression of the disease need more detailed research. The same problem also exists in the other diseases.

The elucidation of these problems is essential for precisely targeting HMGB1 in the treatment of PD. It seems exciting to directly restore the number of healthy dopaminergic neurons in PD by genetic technology or stem cell treatments, and research seems to be increasingly focused in this direction. The positive importance of studying and explaining the existing problems of HMGB1 is not limited to PD. It is critical to answer these questions for all diseases involving HMGB1.

Conclusion

In past decades, strategies to block HMGB1 in animal models of PD have obtained positive evidence in the treatment of traumatic diseases, autoimmune diseases, degenerative diseases, and tumors. Since there are different modifications or forms of HMGB1 in vivo, we cannot completely exclude the upregulation of specific modifications or forms of HMGB1, which may be beneficial in treating diseases. This specific form of HMGB1 exists for a short time in the context of disease. The results do support these points: some forms of HMGB1 and downstream receptors play active roles in preserving TH and clearing α-synuclein. Therefore, more work should be performed to confirm which forms or modifications of HMGB1 have protective effects on diseases and prolong the existence of specific HMGB1 in vivo in the future. Furthermore, interventions for HMGB1 must target specific pathogenic forms.

Acknowledgements

We thank the Springer Nature Author Services editing the revision.

Author Contributions

YT collected information from literatures and wrote the draft. RC read and edited the draft. ZS provided the idea and grant and revised the draft.

Funding

This work was supported by Jiangsu Province “333” project (NO BRA2018016), Primary Research and Development Plan of Jiangsu Province (NO BE2019700), Six talent peaks project in Jiangsu Province (NO 2019-WSN-122), Projects of International Cooperation from Jiangsu (BX2019100), International cooperation and exchange from Zhenjiang (GJ2020010), and Graduate student scientific research innovation projects in Jiangsu province (KYCX18-2283).

Data Availability

All data are obtained from the published papers.

Code Availability

Not applicable.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

All authors approved the final version of the manuscript.

Footnotes

Publisher's Note

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