High mobility group box 1 in the central nervous system: regeneration hidden beneath inflammation

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields, including neurology and neuroscience. High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern, which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, epilepsy, and traumatic brain injury. Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern, such as glycyrrhizin, ethyl pyruvate, and neutralizing anti-high-mobility group box 1 antibodies, are commonly used to target high-mobility group box 1 activity in central nervous system disorders. Although it is commonly known for its detrimental inflammatory effect, high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders. In this narrative review, we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern, its downstream receptors, and intracellular signaling pathways, how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system, and clues on how to differentiate the pro-regenerative from the pro-inflammatory role. Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.