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1. HMGB1 receptor and signal transduction
Although HMGB1-related cellular signal transduction mechanisms are unclear, it has been clear that the receptor for advanced glycation end-products (RAGE) and the toll-like family Of receptors, TLRs) are members of HMGB1. Among them, RAGE was first found as HMGB1 receptor. RAGE had a regulatory effect on HMGB1 expression through JAK / STAT signal transduction pathway. RAGE is a transmembrane protein belonging to the immunoglobulin superfamily, which is widely expressed on different cell surfaces, but the expression level in normal tissue is very low. RAGE expression is increasing when its ligand is aggregated. Ligand binding studies showed that the binding of HMGB1 to RAGE was 7 times higher than that of advanced glycation end products (AGE) and RAGE. HMGB1 promotes chemotaxis through the RAGE receptor pathway and induces inflammatory response by activating NF-kappaB. In the cecal ligation (CLP) animal model, the JAK / STAT pathway was highly activated and the expression of HMGB1 gene was significantly increased in sepsis. Meanwhile, STAT1 and STAT3 increased in liver, lung and intestine according to increased HMGB1 mRNA level. AG490, RPM can down-regulate the activity of STAT1 and STAT3 in multiple organs of CLP, and the expression of HMGB1 mRNA in liver and lung tissues was also decreased. Studying RAGE Receptors Soon after, some experiments found that RAGE blocking antibody or gene knockout did not completely inhibit HMGB1-induced inflammatory response, and extracellular HMGB1 still induced glomerular cell migration and proliferation. Later, DeMarco et al. Found that TLR2 and TLR4 bind to HMGB1 secreted by macrophages and neutrophils, which induce activation of NF-kappaB and induce inflammation, suggesting that TLR2 and TLR4 are receptors for HMGB1. TLRs family members have similar intracellular domain domains, but they specifically bind to receptors. It is worth noting that HMGB1-mediated RAGE activation differs from HMGB1-mediated TLR4 activation. HMGB1-mediated RAGE activation only induces IKKbeta while HMGB1-mediated TLR4 activates IKKalpha and IKKbeta. It has recently been found that individual HMGB1 molecule doesn’t initiate the activation, but rather an HMGB1-DNA complex. Tian et al. Demonstrated that the HMGB1-DNA complex activates the TLR9 signaling pathway and promotes immune cell maturation and cellular secretion through TLR9. It has also been shown that HMGB1-DNA inhibits immune responses in some types of cells. In addition, HMGB1 can also play a role as proinflammatory factor together with other cytokines, such as IL-1beta, TNFalpha.
2. Inhibition of HMGB1 activity
HMGB1 plays an important role in the cascade of inflammation, and inhibition of HMGB1 activity will greatly reduce the mortality of sepsis in mice. Also HMGB1 is involved later than TNF, IL-1, in the process of inflammation. It makes treatment basing on HMGB1 more flexible. That’s why HMGB1 is a potential good target for the anti-infection treatment. Here are some possible ways to inhibit HMGB1 activity.
2.1 HMGB1 antibody:
In the LPS-induced endotoxemia, giving HMGB1 antibody to mouse can significantly reduce the mortality rate. In the CLP model study, Ulloa et al. confirmed that even after 24h since CLP, HMGB1 antibody can effectively inhibit the inflammatory response than the previous TNF antibody and IL-1 antibody better.
2.2 HMGB1 A box:
HMGB1 amino acid polypeptide has A box domain and B box domain. B box mainly plays the role of inflammation and A box antagonist. So A box polypeptide can function as HMGB1 inflammation inhibition. Experiments show that the therapeutic effect is consistent with the treatment of HMGB1 antibody. However, the A box polypeptide is a small and only has short half-life. It need to be modified to stabilize the structure and function better as inhibitor.
2.3 Heat shock protein (HSP):
HMGB1 level in RAW264.7 cells was detected by Western blot after heat shock response (HSR). It was found that HSR could inhibit the release of HMPS1 induced by LPS. The mechanism is not clear. Maybe that HSR or HSPs can inhibit the phosphorylation of MAPK pathway factors such as JNK, ERK and NF-kappaB activity. Or in another way, HSF1 may inhibit HMGB1 expression by binding with HSE (heat shock element) of HMGB1 gene promoter region.
2.4 Ethyl Pyruvate (EP):
Sepsis is a lethal, systemic inflammatory response caused by bacterial infection. It is one of the major causes of death for clinical patients. The cause of sepsis is the excessive release of cytokines and inflammatory mediators, leading to loss of control and immune dysfunction. Therefore, cytokines and inflammatory mediators play an important role in the development of sepsis. Ethyl pyruvate (EP) is a food additive that is classified as a non-toxic substance by the US Food and Drug Administration. It is capable of removing the oxidative product from the body and has a protective effect on ischemia-reperfusion injury in animals. It can improve survival rate of hemorrhagic shock mice. Studies have shown that EP is an effective inhibitor of HMGB1, which can significantly reduce the level of HMGB1 in LPS-stimulated macrophage culture medium and inhibit the release of cytokines such as HMGB1 and TNF-alpha in sepsis mice and reduce sepsis mortality of mice.