This article is about a Swiss Army knife type of protein, and one that you’ve likely not heard a lot about. HMGB1 is a protein and its production takes place in the nucleus of all the cells in the body, but it also has a unique role in activating the inflammatory response pathways. Increased HMGB1 levels will call up the troops for a big response to an infection.
This article explains the different roles of HMGB1, including a key role in the severe SARS-CoV-2 response by some people. We’ll dig into the function of the protein, explore the genetic variants, and conclude with a Lifehacks section explaining ways to modify this response.
HMGB1: From nuclear protein to inflammatory alarmin
HMGB1 (high mobility group box 1) is a multi-functional protein that has several roles, depending on where it is located in the body[ref]:
HMGB1 in the cell nucleus: It is an important chromatin protein, found in all cells. Inside the nucleus, HMGB1 helps to organize the DNA, rearranging it so that different genes can be translated into their proteins. (I’ll explain further in just a minute…)
HMGB1 in the cytosol: Cellular cytosol is within the cell, but outside of the nucleus. Under certain conditions, such as when there is oxidative stress a bacterial pathogen present, HMGB1 moves from the nucleus into the cytosol.
HMGB1 in the serum: The protein is released outside of the cell during trauma, alerting the body to the damage, thus causing a cascade of inflammatory events. Additionally, when inflammatory cytokines are abundant due to a viral or bacterial pathogen, HMGB1 also will be released from immune system cells via extracellular vesicles.[ref] This is referred to as HMGB1 acting as an alarmin, or danger signal.
Background on HMGB1 in the nucleus: DNA must be packaged up tightly so it fits inside the nucleus of cells. But, for any cellular protein to be transcribed and translated, specific segments of the DNA have to open up and be available. There are several ways for the packaging, unpacking, and marking of genes for translation to happen.
The HMGB1 protein is one way this unpacking of DNA can occur — via loosening the packed DNA and bending it so that a gene can be translated. It is part of a family of HMG proteins involved in the way that DNA is unpacked to allow for translation.[ref]
All is good when HMGB1 is in the nucleus, doing its job with translating genes.
HMGB1 gets interesting, though, when it comes to all of its other roles in the body…
HMGB1 and Sterile Inflammation:
HMGB1’s activation occurs in response to damage to a tissue, such as after trauma. It is a molecule for sterile inflammation. When someone gets hurt, the levels of HMGB1 in the plasma rise within 6 hours hours after the trauma.[ref][ref]
Like everything in the immune response, this needs to be kept in balance.
High levels of HMGB1 are associated with multisystem organ failure after trauma.[ref]
After the release of HMGB1, it binds with the receptor for advanced glycation end products (RAGE) activating cytokines such as NF-κB. This starts a feedback loop increasing the production of several different inflammatory cytokines.[ref]
We’ll circle back to RAGE and advanced glycation end products in just a minute…
HMGB1 and Inflammation due to Infections:
HMGB1 is also important for infections, acting as a pro-inflammatory alarmin, or danger signal when the body has been infected by a pathogen.
- Lipopolysaccharide (LPS), which is present on the outside of certain types of bacterial cells triggers the release of HMGB1 from certain immune system cells.[ref]
- Interferons, released due to a viral infection, can also cause the release of HMGB1.
Macrophages, monocytes, and dendritic cells secrete HMGB1 as a mediator of inflammation. It is a signal – an alarm – that something is wrong and causes an increased immune response. Inflammation always needs to be kept in balance – enough response to fight off pathogens but tempered enough to limit the damage. (e.g. sepsis, endotoxemia).
Researchers have found, though, that while HMGB1 acts as a pro-inflammatory signal initially, later in an infection, the large quantities can act as an immunosuppressant. This can lead to a dysregulation of the inflammatory response.[ref]
Delayed: In sepsis, HMGB1 levels rise (up to 300-fold) and reach a plateau more than a day after the onset of septic shock.[ref]
Localized: In peritonitis, researchers found the HMGB1 levels in the abdominal fluid were 10-fold higher than in plasma, indicating that the rise in HMGB1 is localized in the area of infection.[ref]
HMGB1 is important in viral-induced pneumonia also, such as from influenza A. Animal studies show that blocking HMGB1 reduces mortality considerably.[ref]
HMGB1 and Cancer:
Another side of the HMGB1 picture is its role in cancer.
Preventing cell death: When cellular stress that causes increased reactive oxygen species occurs, HMGB1 can move out of the cell nucleus and into the cell. There it helps to sustain autophagy (the recycling of damaged cellular components) and prevents apoptosis (cell death). That is all good — unless that cell has a cancerous mutation. In the case of cancerous mutations, you want the cell to undergo apoptosis and die.
In many cancer types, including breast, lung, and colon cancers, there is an increase in HMGB1.[ref]
Additionally, higher levels of HMGB1 protein can trigger a couple of genes involved in tumor metastasis.[ref]
Researchers are looking at different ways of targeting HMGB1 in cancerous cells.
Again, it is all about balance. There is a trade-off between protecting cells vs. preventing cancerous cells to proliferate.
HMGB1, AGEs, and RAGEs:
Advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGEs) also interact with HMGB1.
This is a huge topic — and you can read more about AGEs and RAGEs here.
In a nutshell, glycation is the binding of a sugar molecule to a protein. This process is on-going in the body, but excessive glycation causes problems. Additionally, glycation end products that accumulate in the body cause some of the damage associated with aging. AGEs and RAGEs are increased in type 2 diabetes.[ref]
The HMGB1 protein binds to RAGE (receptor for AGE), in addition to the toll-like receptors (immune system receptors activated by LPS). Researchers show this by injecting HMGB1 into mice that are lacking various receptors (e.g. RAGE, TLR2) to see the response.[ref]
One way that HMGB1 interacts with RAGE is to bind together with it in order to transport LPS into the lysosomes of a cell. The HMGB1 then causes the lysosome to release the contents into the cytosol, which activates a strong immune response inside the cell resulting in cell death. Again, this can be good in certain situations, but over-activation, such as in sepsis, is bad.[ref]
Why is this interesting?
AGEs and RAGEs elevation occurs in people with diabetes.[ref] This combination may play a role in why people with diabetes are at an increased risk of severe COVID-19 as well as other infections.
Researchers performing a genome-wide CRISPR screen found HMGB1 as a critical component for SARS-CoV-2 replication.[ref]
Other research also shows that HMGB1 may be playing a key role in severe COVID-19 when the immune system is out of control.[ref]
Interferon, which the body produces to combat a virus, can increase HMGB1 release. Cellular stress or cell death, such as in lung cells infected by the virus also causes increased HMGB1 release. The RAGE receptors needed for HMGB1 binding are found in abundance on the alveolar cells in the lungs.[ref]
Previous studies on severe respiratory infections, such as the flu or RSV, show high levels of HMGB1 release. Blocking HMGB1 can stop the severe response (at least in mice, cell studies, etc).[ref][ref]
Again, this may be a matter of timing as to whether HMGB1 needs to be blocked or not. As referenced above, HMGB1 is important in the inflammatory response, but going overboard can cause problems.
HMGB1 and Autoimmune diseases such as lupus:
One more trick up HMGB1’s sleeve is that it also interacts with certain autoimmune conditions, possibly causing the flare-ups in lupus.[ref]
- Some people produce anti-HMGB1 antibodies. In a study of lupus patients, about 23% had anti-HMGB1 antibodies, compared with only 5% of the people in the healthy control group.[ref]
- Another study shows HMGB1 elevation in people with lupus, compared with healthy controls.[ref]
- Mechanistically, lupus is a disease of systemic inflammation, and people with lupus don’t clear out apoptotic cellular debris very well. This causes an increased release of HMGB1.[ref]
HMGB1 and periodontal disease:
Initially in periodontal disease, an increase occurs in epithelial cells releasing cytokines. Animal studies show that HMGB1 release is a critical component of the inflammation that occurs in periodontal disease. Inhibiting HMGB1 with anti-HMGB1 stops the inflammation and bone loss in periodontitis (animal study).[ref]
Again, this isn’t a case where all HMGB1 is bad. For example, the release of HMGB1 after tooth extraction helps to regulate the wound healing process.[ref][ref] Instead, it is the chronic elevation in periodontal disease that seems to be the issue.
Genetic variants of HMGB1:
The HMGB1 gene codes for the HMGB1 protein. Genetic variants in the HMGB1 gene are linked to increased or decreased base levels of the protein. These variants are linked to an increased or decreased risk of the various factors involved in HMGB1 (cancer, inflammation, sepsis, etc).
Check your genetic data for rs1045411 (23andMe v5; AncestryDNA):
Members: Your genotype for rs1045411 is —.
Check your genetic data for rs1412125 (23andMe v4, v5; AncestryDNA):
- C/C: lower risk of lung cancer compared to T/T genotype[ref]
- C/T: most common genotype in many population groups
- T/T: increase risk of community-acquired pneumonia and higher mortality rate, increased HMGB1, IL-6 and TNF-alpha due to bacterial infection[ref]; increased risk for complications with Kawasaki disease[ref]
Members: Your genotype for rs1412125 is —.
Check your genetic data for rs1360485 (23andMe v4, v5; AncestryDNA):
- C/C: increased risk of progression in breast cancer patients[ref]; in patients with EGFR+ lung cancer, a 5-fold increased risk of faster spreading cancer[ref]
- C/T: increased risk of progression in breast cancer patients.
- T/T: most common genotype worldwide
Members: Your genotype for rs1360485 is —.
Note that glycyrrhizin can cause decreased potassium levels, resulting in high blood pressure for some people.[ref]
Recently, it has been proposed that glycyrrhizin may be a good candidate for blocking HMGB1 in cases of severe COVID-19.[ref] Clinical trials are needed to determine whether it would be effective (and safe) or not.
Additionally, mouse studies show that glycyrrhizin can locally stop the inflammation due to HMGB1 release in periodontal disease.[ref]
Nicotine has been shown to inhibit HMGB1 secretion.[ref] This may be why smokers seem to be a paradoxical decrease in the risk of severe COVID-19. (And no, I’m not recommending taking up smoking as a way of inhibiting HMGB1!)
B6 plus amino acids: There is an amino acid compound combined with high-dose vitamin B6 which has been shown to decrease inflammation via inhibiting the HMGB1 pathway. The compound amino acid formula used in research is 20 different amino acids that are in the correct amount needed for the animal or person. Essentially, this is a balanced amino acid profile to correct any deficiencies.[ref]
Other research shows that vitamin B6 may inhibit the toll-like receptors, thus stopping one part of the HMGB1 inflammation pathway.[ref] Foods that include high levels of vitamin B6 include pork, poultry, eggs, beef, tuna, salmon, potatoes, and sweet potatoes.
Decreasing AGE and RAGE: Cooking foods at high heat forms a Maillard reaction – it is that browning reaction that causes things to taste good, like grilled steaks or crispy cookies. Unfortunately, the Maillard reaction also causes an increase in the advanced glycation end products in food, and this corresponds to an increase in AGE in people who eat foods cooked at high heat. You can read all about AGEs, RAGEs, and Lifehacks for preventing formation here.
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