Resistin and related molecules may provide new therapies for sepsis
Researchers from the University of California and the University of Pennsylvania have demonstrated in mice that a human protein provides protection against a life-threatening condition known as "sepsis".
Sepsis refers to the body's extreme response to an injury or infection. Sepsis is among the leading causes of mortality worldwide, and its incidence and mortality rates are rising. In America alone, the disease kills over 250,000 people per year. In the UK, sepsis claims more lives annually than breast, bowel and prostate cancer combined. Resistance to antibiotics is a growing problem, and it's imperative to develop novel sepsis therapies.
Helminths, also commonly known as parasitic worms, have been suggested to counterbalance exacerbated pro-inflammatory immune responses in sepsis and thereby improve survival. A human protein, called resistin, is significantly increased in helminth infection and sepsis. Some suspect that the protein exacerbates infection-associated inflammation. However, the new study shows that the protein may have a protective role in sepsis.
To examine the function of human resistin (hRetn), the researchers employed hRetn-expressing transgenic mice. When challenged by a sepsis-like infection, the transgenic mice had better survival rates than the wild-type mice. This suggests that hRetn may have a therapeutic effect on sepsis.
Using the immunoprecipitation (IP) technique, the researchers discovered that hRetn interacts with the transmembrane protein Toll-like receptor 4 (TLR4) through its N terminal and regulates STAT3 and TBK1 signaling, causing a switch from pro-inflammatory to anti-inflammatory responses.
TLR4 is a cell surface receptor, and its activation is critical for innate immune functions. It's well-established that TLR4 recognizes lipopolysaccharide (LPS), the major structural component of the outer membrane of Gram-negative bacteria. LPS is one of the triggers of the pathogenesis of sepsis and septic shock. Administration of LPS to mice induces inflammatory responses similar to those occurring during septic shock.
In the further research, the researchers produced hRetn N-terminal peptides and found that these peptides could suppress LPS-induced inflammatory responses by blocking TLR4. The smaller size of these peptides makes them more effective than hRetn.
Taken together, the data show that hRetn inhibts LPS-TLR4 interaction and protects against sepsis. hRetn protein and hRetn N-terminal peptides may have a therapeutic effect on the severe disease. In addition, the study provides an explanation for helminth protection against sepsis.
The study (Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction) is published online before print in the Proceedings of the National Academy of Sciences. Dr. Meera Naira, associate professor of biomedical sciences at the University of California, is the corresponding author.
According to Dr. Naira, sepsis therapies like antibiotics are focused on eliminating bacteria while LPS is left behind and causes harmful inflammation. hRetn and similar molecules could inhibit this inflammation and provide new therapy options for patients with sepsis. This is significant given that antibiotic resistance is an increasingly serious problem.
Sepsis and septic shock can result from an infection anywhere in the body, particularly infections that occur in the lungs, the abdomen, and the urinary tract. About one-third of people with sepsis die, and many survivors are left with long-term disabilities.
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