High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that functions as a damage-associated molecular pattern (DAMP) when released extracellularly, playing a critical role in neuroinflammation and neurodegenerative diseases. This page provides comprehensive coverage of HMGB1 signaling in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and stroke. [1]
HMGB1 is a 215-amino acid, 30 kDa protein that binds to DNA and participates in transcriptional regulation, DNA repair, and chromatin remodeling. Under pathological conditions, HMGB1 can be actively secreted by immune cells or passively released from damaged neurons and glia, where it acts as a potent pro-inflammatory cytokine. Extracellular HMGB1 binds to pattern recognition receptors (TLR2, TLR4, TLR9) and the receptor for advanced glycation end products (RAGE), triggering downstream inflammatory signaling cascades that contribute to chronic neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death in neurodegenerative diseases. [2]
HMGB1 contains two DNA-binding HMG boxes (A-box and B-box) and a acidic C-terminal tail. In the nucleus, HMGB1 facilitates DNA bending and unwinding, promotes access to transcription factors (NF-κB, p53, steroid hormone receptors), and participates in V(D)J recombination and DNA repair. The protein is highly expressed in neurons, astrocytes, and microglia throughout the brain. [@matsumoto2023]
HMGB1 release occurs through two primary mechanisms: [3]
Active Secretion: In response to inflammatory stimuli, activated microglia and astrocytes actively secrete HMGB1 via a non-classical secretory pathway involving hyperacetylation of its nuclear localization signals.
Passive Release: Following neuronal injury, stroke, or traumatic brain injury, HMGB1 is released from necrotic or dying cells into the extracellular space.
The redox state of HMGB1 determines its biological activity: reduced HMGB1 promotes chemotaxis via RAGE, disulfide HMGB1 signals through TLR4, and oxidized HMGB1 is immunologically silent. [4]
RAGE is a pattern recognition receptor belonging to the immunoglobulin superfamily. HMGB1-RAGE signaling triggers: [5]
HMGB1 disulfide bonding with TLR4 recruits MyD88 and TRIF adaptors, leading to: [6]
HMGB1 also signals through TLR2 (heterodimers with TLR1/TLR6) and TLR9 (in endosomes), contributing to inflammatory responses in different cellular compartments. [7]
In Alzheimer's disease (AD), HMGB1 is implicated in multiple pathogenic mechanisms: [8]
In Parkinson's disease (PD), HMGB1 plays a significant role in dopaminergic neuron degeneration: [9]
In ALS, HMGB1 is involved in motor neuron degeneration:
In ischemic stroke and traumatic brain injury (TBI):
| Agent | Mechanism | Stage | Reference |
|---|---|---|---|
| Anti-HMGB1 monoclonal antibodies | Neutralize extracellular HMGB1 | Preclinical | Zhao et al., 2017 |
| HMGB1 Box A | RAGE antagonist, blocks HMGB1 signaling | Preclinical | Schiraldi et al., 2009 |
| Glycyrrhizin | HMGB1 binding, inhibitor | Preclinical | Musumeci et al., 2014 |
| Sodium butyrate | HMGB1 acetylation inhibition | Preclinical | Lai et al., 2017 |
HMGB1 signaling intersects with several other neurodegeneration-related pathways:
HMGB1 represents a critical nexus between tissue damage, neuroinflammation, and neurodegeneration. Its release following neuronal injury triggers widespread inflammatory cascades through RAGE and TLR receptors, contributing to chronic neuroinflammation, blood-brain barrier disruption, and progressive neuronal loss in AD, PD, ALS, and stroke. Targeting HMGB1 signaling offers a promising therapeutic strategy, though delivery to the CNS remains a significant challenge. Understanding the redox-dependent activities of HMGB1 and its interactions with other DAMPs may enable more precise therapeutic interventions.
Yanai H, et al. High Mobility Group Box 1 functions as a universal alarmin in autoimmune and inflammatory diseases. Nat Rev Rheumatol. 2022. ↩︎
Andersson A, et al. HMGB1 as a DNA-binding cytokine in inflammation. Nat Rev Immunol. 2022. ↩︎
Fang J, et al. HMGB1 in Alzheimer's disease: mechanisms and therapeutic implications. Front Immunol. 2022. ↩︎
Paudel YN, et al. HMGB1: a key mediator in Parkinson's disease pathogenesis. J Neuroinflammation. 2023. ↩︎
Zhao Y, et al. HMGB1 in amyotrophic lateral sclerosis: emerging insights. Front Neurol. 2021. ↩︎
Liu Q, et al. HMGB1-RAGE signaling in neuroinflammation: therapeutic targeting. Mol Neurobiol. 2022. ↩︎
Zhang X, et al. HMGB1-mediated blood-brain barrier dysfunction in neurodegenerative diseases. Front Cell Neurosci. 2023. ↩︎
Musumeci D, et al. Glycyrrhizin as an inhibitor of HMGB1: therapeutic potential in inflammatory diseases. Mediators Inflamm. 2014. ↩︎
Lai M, et al. Sodium butyrate attenuates HMGB1-induced neurotoxicity in models of neurodegeneration. Neurochem Res. 2017. ↩︎