High Mobility Group Box 1 (HMGB1) is a protein found within nearly all cells of the body. It plays a role in various cellular processes when inside the cell. However, when HMGB1 is released from cells, it acts as a signal that can trigger and sustain inflammatory responses throughout the body. This dual function positions HMGB1 as a factor in both normal bodily functions and in the progression of numerous health conditions linked to inflammation.
Understanding HMGB1
HMGB1 is a highly conserved protein, its structure largely unchanged across many species. It is located within the nucleus of cells, where it associates with DNA. Inside the nucleus, HMGB1 helps organize DNA, influencing the overall structure of chromosomes and regulating gene expression. This internal role maintains cell integrity and proper cellular function.
When cells are damaged, stressed, or undergo programmed cell death (necrosis), HMGB1 can be released into the extracellular space, outside of cells. In this external environment, HMGB1 transforms from an intracellular protein into a “danger signal” or alarmin. This release signals tissue damage or a threat to the immune system, prompting an immune response.
How HMGB1 Triggers Inflammation
Extracellular HMGB1 promotes inflammation through several mechanisms. It is actively secreted by immune cells, such as macrophages, monocytes, dendritic cells, natural killer cells, platelets, and endothelial cells, in response to stimuli like bacterial products (lipopolysaccharide, LPS). HMGB1 is also passively released from cells undergoing necrosis, a form of uncontrolled cell death during tissue injury.
Once outside the cell, HMGB1 interacts with receptors on immune cells, initiating inflammatory pathways. Primary receptors involved are Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and the Receptor for Advanced Glycation End products (RAGE). Disulfide HMGB1, a specific modified form, activates the TLR4 complex, leading to the production of pro-inflammatory cytokines such as TNF-α and IL-6. The binding of HMGB1 to RAGE also activates signaling pathways, including NF-κB and MAPK, which promote the production of inflammatory mediators.
This interaction with receptors activates intracellular signaling cascades, triggering the production and release of pro-inflammatory cytokines and chemokines. These molecules, such as TNF-α, IL-1β, IL-8, and MCP-1, amplify the inflammatory response by recruiting immune cells to the site of injury or infection and promoting their activation. For instance, HMGB1 can induce the expression of adhesion molecules like ICAM-1 and VCAM-1 on endothelial cells, facilitating the movement of leukocytes into inflamed tissues.
HMGB1’s Role in Various Health Conditions
Dysregulated or sustained HMGB1 release contributes to the pathology of acute and chronic inflammatory diseases. In sepsis, a severe response to infection, elevated HMGB1 levels are observed in patients and animal models. HMGB1 promotes organ dysfunction in sepsis by suppressing neutrophil ability to clear bacteria, leading to persistent inflammation and immunosuppression in later stages.
HMGB1 also plays a role in autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. In these conditions, ongoing HMGB1 release can perpetuate chronic inflammation by continuously activating immune cells and driving inflammatory cytokine production. For example, in allergic rhinitis, HMGB1 contributes by disrupting the nasal epithelial barrier and promoting immune responses through RAGE and TLR4 pathways, leading to the release of cytokines like IL-4, IL-5, IL-13, and IL-17A.
In neuroinflammation, HMGB1 is implicated in conditions like stroke and Alzheimer’s disease. Following a stroke, HMGB1 released from damaged brain cells contributes to secondary brain injury by exacerbating inflammation. HMGB1 is also released by tumor cells and activated macrophages in certain cancers, promoting inflammation in the tumor microenvironment. While inflammation is a protective process that helps the body heal, chronic or uncontrolled HMGB1-driven inflammation is detrimental, leading to tissue damage and disease progression.
Targeting HMGB1 for Treatment
Given its role in inflammation, HMGB1 has emerged as a potential therapeutic target for various inflammatory diseases. Strategies aim to neutralize HMGB1 or block its activity. One approach involves neutralizing antibodies against HMGB1, which have shown beneficial effects in preclinical models of inflammatory diseases, including sepsis and collagen-induced arthritis. These antibodies mitigate septic damage and inhibit the release of other pro-inflammatory cytokines.
Another strategy focuses on small molecule inhibitors that block HMGB1 release from cells or interfere with its extracellular activity. For instance, compounds like ethyl pyruvate inhibit HMGB1 by interfering with its export from the cytoplasm, while glycyrrhizin directly binds to HMGB1, making it unavailable to its receptors. Antagonists that block HMGB1’s interaction with its receptors, particularly RAGE and TLR4, are also investigated. These antagonists aim to interrupt signaling pathways that lead to inflammatory responses.
The recombinant HMGB1 Box A protein, a DNA-binding motif of HMGB1, acts as an antagonist and has demonstrated beneficial effects in preclinical models of inflammatory diseases. These therapeutic approaches are areas of ongoing research and clinical trials, representing future possibilities rather than widely available treatments. Further understanding of HMGB1’s modified forms and their specific activities may lead to more targeted and effective therapies.