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Scientists decipher the role of a gene that kicks off our immune response

Each day, we come across potentially infectious microorganisms in our environment. Yet, how is it that we don't fall sick and stay in bed all the time?  Thanks to our immune system, which has a wide range of cells in its arsenal to combat and clear away any pathogens, we are safe. Of these cells, macrophages, or ‘big eaters’ in Greek, act like vacuum cleaners by engulfing pathogens in our body and clearing up the cellular debris left behind. In a recent study, researchers at the CSIR-Institute of Microbial Technology (CSIR-IMTECH), Chandigarh, have discovered the role of a gene that regulates how these macrophages respond to different pathogens and help our immune system.

Macrophages, a type of white blood cells, play a vital role in an organism's life; from its development and maintenance to its repair and protection. However, at times, they could go out of control and start attacking the cells of the organism they have been designed to protect, resulting in diseases such as cancer and other autoimmune disorders. In this study, the researchers have discovered the very first cellular function for the tumour suppressor gene ARL11, which was unknown so far. The study is published in published by The Journal of Biological Chemistry and is funded by Wellcome Trust/DBT India Alliance fellowship.

“The gene encoding the protein ARL11 is frequently turned ‘off’ or mutated in cancer cells. However, when a functioning ARL11 gene is inserted into lung cancer cells, the cells die. These types of evidence have led scientists to categories the gene as a tumour-suppressor protein. However, it was almost completely unknown what ARL11’s fundamental role was in healthy cells and healthy organisms. This is the first study showing the function of the gene in controlling the activity of macrophages”, says Dr Amit Tuli from CSIR-IMTECH and an author of the study in an interview with Research Matters.

The researchers studied macrophages by suppressing or turning ‘off’ the ARL11 gene. They found that the activation of these ‘ARL11-silenced’ macrophages was a lot lesser than the healthier ones. They also produced lower levels of inflammatory cytokines—proteins that cause inflammation during an infection—and were defective in phagocytosis—the process of engulfing a pathogen to destroy it. Both these qualities are necessary to defend the body against an attack by a pathogen. The researchers also discovered that Salmonella typhimurium, the bacterium that causes typhoid in mice, was able to survive and proliferate in the defective macrophages.

So, how does ARL11 help in maintenance of macrophage functions? Previous studies have shown that macrophages are activated through a cascade of complex signalling reactions involving several proteins and other immune effector molecules—molecules that bind to a protein and regulates its activity. The researchers of the current study show that the protein encoded by the gene ARL11 is a critical player in this signalling cascade. As a response to an encounter with a pathogen, the ARL11 gene activates the signalling pathways that are involved in the activation of macrophages, and in turn, controls the response of macrophages against pathogens.

“In this study, we also found that ARL11 appears to act by initiating a signalling cascade which is known to regulate the division of cells and is therefore implicated in cancer. Depending on whether the pathway is turned on briefly or for extended lengths of time, cells either proliferate or die. This connection probably underlies Arl11's connection to cancer, which the research team is now exploring”, comments Dr Tuli.

The findings of this study have broad implications as macrophages, which play a vital role in causing cancer and other inflammatory diseases, could hold the key to new avenues of immunotherapy. The researchers plan to further their efforts in thoroughly studying the ARL11 gene. “In the present study, we only looked at the impact of silencing ARL11 on the growth of Salmonella. In the future, we plan to look at its impact on the replication of Mycobacterium tuberculosis”, signs off Dr Tuli.