HMGB1: a potential mechanistic direction in depression
HMGB1 is the most researched protein in the HMGB family for inflammation as innate immune responses. Expressed in nearly all eukaryotic cells, HMGB1 is a kind of chromatin-binding molecule to function in chromatin remodeling in the nucleus under normal physiological situations. Whereas in stressful situations or pathological situations, caused by immune and other cells or cell injury and death, HMGB1 secretes or translates from nuclei to the cytoplasm and eventually excretes or releases to the extracellular milieu, acting as a mediator of inflammation extracellularly. Placing on extracellular milieu, HMGB1 is acknowledged by plenty of binding receptors, mainly including Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE), resulting in the expression of proinflammatory response elements and eventually in the inflammatory cascade. The TLRs and RAGE are transmembrane proteins, which are located in the membrane of several cells such as monocytes, macrophages, dendritic cells, and neural cells. For the HMGB1-TLRs pathway (mainly including TLR2 and TLR4), MyD88 dependent and independent pathways were activated, resulting in the simulation of NF-κB and induction of pro-inflammatory response. For MyD88-dependent pathway, MyD88 serves as a domain-containing adaptor for the cytoplasmic Toll/ interleukin (IL)-1 receptor. Stimulated by ligands, MyD88 recruits IL-1 receptor-associated kinase-4 (IRAK-4) to TLRs; and IRAK-1 is phosphorylated and then associates with TRAF6, thereby activating the IKK complex and leading to activation of MAP kinases (JNK, p38 MAPK) and NF-κB[21,22]. The MyD88-independent pathway also mediates the immune response via TRIF and TRAF3, leading to recruitment of IKKε/TBK1, phosphorylation of IRF3, and expression of interferon-β[23,24]. A recent study also indicated that the HMGB1-TLR4 pathway could activate Nod-like receptor protein 3 (NLRP3) inflammasome and then enhanced the production of IL-1β. For the HMGB1-RAGE pathway, the downstream signaling is propagated by the Akt, MAPK, ERK, JAK-STAT1, and Rac pathways, ultimately promoting the activation of NF-κB and expression of the proinflammatory cytokines and chemokines, which contributes in the immune cells’ maturation and migration and surface receptors’ expression[26,27]. Fully reduced HMGB1 (fr-HMGB1), which is a kind of three redox states (fr-HMGB1, disulfide HMGB1, and sulfonyl HMGB1), can act as a chemoattractant through connections with RAGE. Furthermore, binding with C-X-C motif chemokine receptor 4, promotes chemotactic activity (stimulates leukocyte recruitment). It should be noted that such inflammation activation can lead to inflammatory responses and cell injury and death, which promotes the further release of HMGB1 and upgrade of its receptors. This may contribute to the aggravation and drug-resistance of HMGB1 related disease.
More recently, neuroinflammation has been proposed to play a significant role in several diseases including depression, epilepsy, stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease[11-15]. HMGB1 is considered as an essential neuroinflammatory facilitator, which is released by glial cells and neurons upon inflammasome activation and acts as a pro-inflammatory cytokine. Neurons are considered as a primary and necessary driver of neuroinflammation through release of HMGB1, with the subsequent amplification via recruitment of immunocompetent cells, including microglia and astrocytes. HMGB1 has been proved that it releases from neurons in many central nervous system (CNS) diseases and then triggeres neuroinflammation as an upstream inflammatory mediator[15,32]. Activated by HMGB1, microglia functions as key contributor of the inflammatory processes sequentially influences neural cells, following by the activation of microglial NF-κB pathway and production of pro-inflammatory cytokines. The study of Gao et al using a Parkinson's disease model revealed that HMGB1 released from inflamed microglia and/or degenerating neurons, bound to microglial Mac1 and activated NF-κB pathway and nicotinamide adenine dinucleotide phosphate oxidase to stimulate production of multiple inflammatory and neurotoxic factors. Astrocytes are also a population of CNS cells with distinctive morphology and functions. Xiao et al suggested that HMGB1 promoted the release of sonic hedgehog from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE in an animal model of multiple sclerosis, suggesting the important role of HMGB1-astrocytes medicated neuroinflammation. Also, some types of reactive astrocytes can also be induced by activated neuroinflammatory microglia and take parts in various human neurodegenerative diseases, formulating a complex immune network.
Depression is also found to closely link with neuroinflammation, which is mainly characterized by the increased mediators of inflammation and neurodegeneration. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules, including IL-1β, IL-6, TNF-α and CRP[38,39]. Preclinical study based on animals also exhibited the activation of microglia together with enhanced inflammatory mediators. In a chronic mild stress (CMS) mouse model of depression, NLRP3-inflammasome/caspase-1/IL-1β axis microglia-mediated neuroinflammation was found being activated. Another study suggested rats exposed to CMS exhibited a significant increase in inflammatory mediators, including TNF-α and IL-1β, activation of NF-κB signaling pathway in the hippocampus. Icariin, a flavonoid inhibiting neuroinflammation, could negatively regulated the activation of the NLRP3 inflammasome/caspase-1/IL-1β. Chronic treatment with corticosterone and intraperitoneally administration of lipopolysaccharide depressed models also showed a higher expression level of pro-inflammatory phenotype characterized by IL-1β, IL-6, TNF-α and IκB-α[42,43]. These findings provide a powerful connection of neuroinflammation and depression.
Concerning HMGB1 medicates depression, recent studies suggested that HMGB1 might be a probable inducer of stress-mediated neuroinflammation in depression. It has been proven that HMGB1 could activate neuroinflammatory reactions by inducing TNF-α to exhibit anhedonia-like behavior. Based on the inescapable tail shock rats’ model, Weber et al indicated that HMGB1 in the brain is a probable inducer of stress-mediated microglial priming by acting on the NLRP3 inflammasome and pro-inflammatory cytokines. Based on recent studies, stress-mediated depression-like behaviors were found to be induced by HMGB1 and glycogen synthase kinase-3 dependent TLR4 signaling, resulting in the activation of NF-κB and NLRP3 inflammasome; and the HMGB1 was additionally promoted in mice. This stress-induced neuroinflammation can further make it more susceptible to depression. Based on rats’ chronic unpredictable stress (CUS)-induced behavioral deficits, Franklin et al discovered that CUS caused consistent upregulation of HMGB1 mRNA and RAGE mRNA in hippocampal microglia. They also found that HMGB1 infusion into the hippocampus caused anhedonic behavior and suggested that HMGB1-RAGE increased vulnerability to depressive-like behaviors long[10,48]. In addition, HMGB1 could also induce depressive behaviors by limiting the kynurenine pathway via suppression of activated enzymes. Furthermore, based on preclinical studies, neuroinflammation induced by HMGB1 can mediate depressive behaviors such as reduction of locomotor activity and sucrose preference, which are analogs to the motivational deficits in depression[49,50].
HMGB1: a potential therapeutic target in depression
Current studies proposed that interventions in the HMGB1 and related molecular in its neuroinflammation pathways have the potential to be a therapeutic target in several diseases like depression, epilepsy, cancers, stroke, and other local and systemic neuroinflammatory diseases[4,13,15]. The main potential therapeutic targets include anti-HMGB1 monoclonal antibody (mAb), HMGB1 inhibitors, and HMGB1 receptors and its related molecular in neuroinflammation pathway.
For depression, although several studies provided evidence on mediating HMGB1, this topic is still needing more effort. Traditionally commonly used anti-depression drugs based on the theory of serotonin-like selective serotonin reuptake inhibitors (SSRIs) as well as serotonin and norepinephrine reuptake inhibitors may be complicated to treat motivational deficits symptoms, suggesting additional neurotransmitters like dopamine dysfunction might be involved[51,52]. Also, recent studies suggested the anti-inflammatory and anti-oxidative effects may be one of the potential mechanisms of these anti-depression drugs. Only limited studies are based on animal models concerning the therapeutic target of HMGB1 in anti-depression. Liu et al and Fu et al indicated that the anti-depressive-like behavior compound Hesperidin and Baicalin reduced the CUS-induced model by inhibition of neuroinflammatory actions via HMGB1-TLR4-NF-κB pathway or HMGB1-RAGE-NF-κB pathway. The anti-HMGB1 mAb is highly specific for HMGB1, which shows the value of target validation but also has potential for the treatment of neuroinflammation diseases, including depression. Hisaoka-Nakashima et al used the model of partial sciatic nerve ligation to introduce neuropathic pain and anxiodepressive-like behaviors in mice. They observed increased HMGB1 and microglia activation in the frontal cortex. Anti-HMGB1 mAb and glycyrrhizic acid (HMGB1 inhibitor) can reduce microglia activation and anxiodepressive-like behavior. HMGB1 inhibitors can be another possible anti-HMGB1 strategy. Based on the CUS-induced model both in vivo and in vitro, glycyrrhizic acid, the inhibitor of HMGB1, may restrain HMGB1 thus improving depressive-like behaviors through regulating the kynurenine pathway[47,56]. Encouragingly, a recent clinical trial found that depressive symptoms are relieved more in SSRI+ glycyrrhizic acid than SSRI+ placebo, proving anti-inflammatory agents is effective in clinical use. The HMGB1 receptors and their related molecular in neuroinflammation pathway can also be a therapeutic target. Cheng et al based on an inescapable tail shock model suggested that TLR4 knockout mice were resistant to learned helplessness and GSK3 (a TLR4 signaling dependent kinase) inhibitor TDZD-8 reduced the stress-induced increases of hippocampal cytokines and chemokines.
HMGB1: summarize of HMGB1 in depression
Based on current studies, HMGB1 may be a possible signaling inducer of stress-mediated depression behaviors via HMGB1-TLRs signaling and HMGB1-RAGE signaling, followed by the activation of NF-κB and expression of the proinflammatory cytokines and chemokines, resulting in the neuroinflammation procedure. This pathway suggests a possible mechanistic direction for depression. HMGB1 can also be a potential therapeutic target in depression by playing an important role in neurotransmitter-related anti-depression drugs, anti-HMGB1 mAb, HMGB1 inhibitors, and HMGB1 receptors. However, there are still many challenges in further exploring HMGB1 as a potential mechanistic and therapeutic direction. The mechanistic illustration of HMGB1 in depression is provided as Figure 1.
Figure 1 Illustration of mechanistic and therapeutic perspective of high mobility group box 1 in depression.
HMGB1: High mobility group box 1; TLRs: Toll-like receptors; RAGE: Receptors for advanced glycation end products; CXCR4: C-X-C motif chemokine receptor 4.