Molecular sensors enable eukaryotes to recognize microbial pathogens and their products, thus operating as major players in the protective mechanisms of the innate immune response. In addition to microbial pathogens, innate molecular sensors recognize signals from damaged tissues. The response of innate molecular sensors is typically immediate but short-lived. However, excessive activation and/or engagement of sensors by self molecules (as in the case of damaged tissues) may induce autoimmunity and other inflammatory disorders.
Now, a very recent study (published today, April 16, 2019!) in the scientific journal eLife highlights a new function for one of these sensors. The sensor, called NLRP12, is a member of the NOD-like family of pattern recognition receptors, and is located in the cytosol of innate immune cells. It is also known to be a critical regulator of inflammation and cancer. The new study (NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte) shows that NLRP12 has a protective effect against hepatocellular carcinoma, a deadly human cancer.
Hepatocellular carcinoma is the most common type of primary liver cancer. It occurs most often in people with chronic liver diseases, such as cirrhosis caused by hepatitis B or hepatitis C infection, and in people who drink large amounts of alcohol and who have an accumulation of fat in the liver. Although the precise mechanisms through which these conditions induce liver cancer are unknown, chronic inflammation in the liver is considered a key player.
For the study, researchers exposed mice that were missing the Nlrp12 gene to a chemical carcinogen. Results show that these mice exhibit higher levels of inflammation and increased tumor development compared with normal mice. Therefore, the researchers examined the signals sent by tumor cells in mice with and without the Nlrp12 gene. They found that the JNK (c-Jun N-terminal kinase) pathway, which is known to be associated with liver cancer, is highly active in liver tumors that lack Nlrp12.
The JNK pathway is usually activated by a component of bacterial cell walls called lipopolysaccharide (LPS). Both “good” bacteria (which line the gut and aid in digestion) and “bad” pathogenic bacteria are able to release LPS. Once released, LPS can travel from the gut to the liver via the bloodstream. In the liver, LPS can participate to the development of inflammation by setting off the JNK and other signaling pathways. LPS transport is much more common in chronically inflamed livers such as those of people suffering from hepatitis or fatty liver disease.
All together, these results suggest that NLRP12 suppresses inflammation caused by gut microbiota, and inhibits cancer-promoting signals and proliferation of hepatocytes.
To confirm the gut-liver inflammation-cancer hypothesis, the researchers treated mice with antibiotics to reduce levels of gut bacteria. Dr. Hasan Zaki, senior author of the study, said in a press release: “Depletion of gut microbiota with antibiotics dramatically reduced tumor growth in mice without Nlrp12. This study suggests that NLRP12 could be a potential therapeutic target. It also indicates that finding a way to increase NLRP12 in the liver in combination with current immune checkpoint blockade therapies may improve liver cancer treatment.”