by Jalees Rehman
How can we toggle the immune system’s “off switch”? How do we deactivate the cells and molecules which form an essential line of defense for our body and protect us against invading pathogens once their job is done? Persistent inflammation after pathogens are eliminated can be very harmful to the body because oxidants and other injurious molecules produced by immune cells end up attacking the body’s own tissues and organs instead of the pathogens.
During an infection, immune cells become activated and mount an inflammatory response against harmful bacteria and viruses. Inflammation in a tissue or organ entails an increase in the number of immune cells which is achieved by the release of chemokines – molecules which beckon fellow immune cells to the sites of infection and inflammation – as well as the upregulation of molecules such as oxidants which help eliminate pathogens as well as important protein molecules. Some of the molecules released by immune cells – such as the protein interleukin 1β (IL-1β) – amplify inflammation and also cause fever, which is thought to improve the ability of our immune system to fight. In the case of bacterial infections, our immune system may be overwhelmed by the invading bacteria and thus needs the help of antibiotics which directly kill bacteria. Appropriate antibiotic treatments combined with the valiant efforts of a healthy immune system are usually sufficient to get rid of most pathogens. Once they are eliminated, the inflammation then subsides. The immune system switches into a cooling off mode, at which point immune cell numbers decrease and their attack activity diminishes.
Unfortunately, the immune system does not always stand down from an inflammation mode. Instead, immune cells remain hyper-activated in some patients and continue to engage in a fight even after the pathogens have been eradicated.
A classic case of the immune system gone awry is the phenomenon of acute respiratory distress syndrome (ARDS), a complication of severe pneumonias and blood stream bacterial infections, in which immune cells cause such severe injury to the lung that patients end up requiring oxygenation through a ventilator in order to survive. Such incessant inflammation is very difficult to treat because it poses major dilemmas. Suppressing the immune cells would diminish the inflammation but at the same time it would also make the body more vulnerable to any residual pathogens that may be surreptitiously lurking in the body and could engage in resurgence in the face of a diminished immune system. Furthermore, patients could be especially vulnerable to new infections if their immune system was suppressed and they could also suffer from additional side effects of anti-inflammatory drugs such as their known propensity to affect kidney function in some patients.
Searching for new ways to suppress excessive inflammation is therefore a major challenge for biomedical research. Having a larger repertoire of tools to control the immune response would allow physicians to individualize treatments, ideally choosing a drug with a side effect profile that is least likely to harm the patient suffering from excessive inflammation after an infection. During the past years, my laboratory collaborated on a research project lead by my colleague Dr. Asrar Malik, Professor and Chair of Pharmacology at the University of Illinois at Chicago to address this problem. In this project, our team identified a novel role for a molecule regulating inflammation in selected immune cells during a severe infection. The results of the study were published in the journal Immunity.
The research was based on an observation made by Dr. Malik’s lab that there is a flow of an electrical current by potassium ions in activated macrophages, an important group of immune cells involved in the response to bacterial infections. Using cellular and molecular tools, we found that the ion channel enabling the flux of potassium channels was TWIK2, which had been previously found in other cell types but not studied in immune cells. Interestingly, we found that the drug quinine which has been used for centuries as a drug to treat malaria and other tropical fever illnesses blocked the electrical current through the TWIK2 channel and also prevented the release of the fever-induced and inflammation-amplifying molecule interleukin 1β. Mice which genetically lacked the TWIK2 channel had a much better controlled response to bacterial bloodstream infections and a much greater rate of survival.
How does this research advance our understanding of inflammation and the ability to rein in the immune response? It brings together two areas of biomedical research: 1) electrical currents through channels that are commonly studied in heat cells and brain cells and 2) the regulation of inflammation amplifying molecules such as interleukin 1β. This suggests that drugs that may have been developed or are in development for affecting electrical currents by potassium ions could be repurposed for treating inflammation. There is also the possibility that suppressing the release of the inflammation amplifier interleukin 1β by diminishing the function of the TWIK2 channel may selectively reduce excessive inflammation without hampering the overall immune function. Our research could explain in part why the classic drug quinine suppresses fever but it also paves the way for developing newer, targeted anti-inflammation therapies.
Our work is just at the preliminary stages which rely on detailed electrophysiological and molecular analyses in mice. We do not know yet whether blocking the TWIK2 molecule will be just as effective in improving the survival following severe infections in larger animals or in humans. It is also possible that blocking an ion channel could have side effects such as affecting heart rhythms which rely on a specific sequence of ion channel activation. But the possibility that there may be new ways to target hyper-inflammation is very exciting and we believe that this research represents a promising new avenue in inflammation research.
Reference
Di A et al. (2018). “The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation” Immunity