Infection by Gram-negative bacteria is a serious threat to human health. It is known to cause infection and disease in humans and other animals, and it can also result in the accumulation of cytosolic lipopolysaccharide (LPS) and the activation of the non-canonical inflammasome, leading to pyroptotic cell death. Although this process has been proposed to occur without a dedicated LPS-sensing pattern recognition receptor, a new study by Rojas-Lopez et al. uncovered an important component of the process. Specifically, they found that the primate-specific protein NLRP11 is required for effective cell death after infection of human macrophages by the bacterial pathogen Shigella flexneri.
NLRP11 has an important role in non-canonical inflammasome activation, and genetic deletion of NLRP11 impaired this process. The study also showed that NLRP11 can bind both LPS and caspase-4, two molecules that are necessary for successful non-canonical inflammasome activation.This study provides an important insight into the process of LPS-mediated cell death in human macrophages. It has long been known that LPS is essential for this process, but until now it was unclear how it was sensed by the cell. This study demonstrates that NLRP11, a primate-specific protein, can act as a pattern recognition receptor and is essential for efficient caspase-4–mediated cell death in human macrophages.
The findings of this study are important for understanding how infection by Gram-negative bacteria leads to disease and death in humans. By better understanding the molecular mechanisms involved in this process, researchers can develop new therapies and strategies for preventing and treating infections caused by these bacteria. It is also an important step in developing new treatments for diseases such as sepsis, which is caused by an overactive immune response to infection. In summary, this study provides valuable insights into the process of infection by Gram-negative bacteria and its effects on human health. The discovery of NLRP11 as a pattern recognition receptor is an important step towards developing effective treatments for infections caused by these bacteria.
The primate-specific protein NLRP11 is a pattern recognition receptor for cLPS.
Endotoxin, a bacterial lipopolysaccharide (LPS), is a major driver of lethal sepsis infections through excessive activation of the innate immune system. When delivered directly to the cytosol of macrophages, it induces the assembly of an inflammasome. This inflammasome contains caspases-4/5 in humans and caspase-11 in mice. Up until now, however, it has remained unclear whether or not pattern recognition receptors for cLPS exist.
A new study has revealed that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS that is required for efficient activation of the caspase-4 inflammasome in human macrophages. This study found that NLRP11 is necessary for successful activation of caspase-4 when human macrophages were infected with intracellular Gram-negative bacteria or upon electroporation of LPS. Not only that, but NLRP11 was also able to bind to both LPS and caspase-4 independently, forming a high–molecular weight complex with the enzyme in HEK293T cells.
This discovery is especially significant because NLRP11 is only present in primates and not in mice – which explains why it has been overlooked in past studies that have been focused on innate immune signaling molecules. The results of this study demonstrate that NLRP11 is a key component of the caspase-4 inflammasome activation pathway in human macrophages.
This finding has clear implications for sepsis treatment, as understanding more about this pathway could help researchers develop new strategies for treating this potentially fatal condition. Further research into this area could also help us gain a greater understanding of how other inflammatory processes are triggered within the body.
Overall, this new study sheds light on an important aspect of sepsis treatment and adds to our knowledge base on how the innate immune system functions. Understanding more about NLRP11 could help us develop better treatments and therapies for sepsis and other inflammatory conditions.
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