Inflammation, characterized by pain, heat and swelling, is the body’s response to harmful conditions such as infection and cellular damage. Through inflammation, the body ensures the removal of pathogens, dead cells and regeneration of damaged tissue. However, when the inflammation persists for years like in the case of rheumatoid arthritis, atherosclerosis and asthma, permanent tissue damage and even cancer can occur. It has also been found that older individuals have higher levels of inflammation that can persist to chronic levels. In a new study, researchers from the Indian Institute of Science, Bengaluru, have found the mechanism which enhances inflammation and suggest that targeting the molecules that drive this can slow down ageing as well as reduce inflammation due to anti-cancer therapies.
“Inflammation is a response to cellular injury and causes the recruitment of immune cells to the site of injury so that the damaged cells are cleared”, explains Prof. Deepak Saini, whose team led the study, in an interview with Research Matters. “However, if the damaged cells are too many or the immune response is weak, then the inflammation does not resolve and becomes persistent. It can then result in conditions like autoimmune disorders or cardiovascular diseases”, he adds.
The underlying cause of this inflammation is the magnitude of damage, where cells may undergo different processes like repair, cell death, or senescence—an irreversible state of arrested growth known to contribute to ageing. The critical role of inflammation is that it serves as a response to the damage caused to our genetic code, the DNA. However, if the damaged cells are not repaired or cleared, they cause persistent inflammation which is one of the main side-effects of anti-cancer therapy and also causes age related decline in tissue and organ function.
Why is inflammation so harmful, you ask? “Limiting inflammation is not only necessary for improving the quality of life but also to prevent the damaging of healthy cells", reasons Dr. Saini. "Excessive inflammation damages healthy cells, which in turn results in more inflammation. Thus, it is essential to suppress excessive inflammation so that overall damage and systemic injury is limited,” he says. Drugs like Rolipram, which are identified in this study, suppress damage that has been induced by excessive inflammation, can be used as supplementary therapy for those being treated for cancer. It has uses with age-associated disorders and chronic inflammatory conditions like rheumatoid arthritis as well.
In the current study, published in the journal npj Aging and Mechanisms of Disease, the researchers have identified the molecular players that regulate the chronic inflammation caused by DNA damage. The research was funded by the Department of Biotechnology, Department of Science and Technology, Infosys Foundation and the Council for Scientific and Industrial Research, India.
When the researchers mimicked chronic inflammation in mice using chemotherapeutic agents and exposure to radiation, they found that the DNA damage resulted in senescence and the production of a protein called CXCR4. Normally, this protein is involved in development and movement of immune cells. High levels of CXCR4 has also been linked to the spreading of tumors to other parts of the body. Interestingly, they found that the same protein, CXCR4 was also increased in older cells and mice when compared to young ones. Using a library of FDA approved compounds, the group was able to identify drugs that could specifically target and reduce the inflammation caused by CXCR4 in the context of DNA damage. Another finding from the study is that CXCR4 is always produced in high amounts whenever there is any kind of stress that produces DNA damage like in the case of very aggressive cancers or after cancer chemotherapy. Thus, this protein can be used as a universal marker indicative of DNA damage within the cell. The study explains that while CXCR4 is not involved in initiating inflammation, its presence in cells with damaged DNA leads to enhanced inflammation and accelerated aging.
To sum up, the discovery that blocking CXCR4 and the pathways associated with it can reduce inflammation and tissue injury and has the potential to enable safer and more effective anticancer therapies by protecting the non-cancerous cells surrounding the tumour from prolonged inflammation and damage. Also, this pathway can be explored further to potentially reduce inflammation associated with ageing and allow individuals to age more gracefully.
“We are presently aiming to understand how and why aged cells stay alive despite being damaged, rather than being cleared by the immune system. Other avenues of our research include the development of senolytic approaches (the removal of senescent cells), which have been shown to improve quality of life in aged animals or develop seno-suppressants which prevent inflammation during ageing,” says Prof. Saini on the future of this research.