Curb Your Inflammation

The body’s inflammatory response is crucial for combating invading pathogens, but sometimes this response spins out of control, leading to chronic disease or even death. Several recent studies now uncover transcriptional mechanisms that help to hold inflammation in check. A rather extreme example of inflammatory overkill is sepsis, in which the body mounts an excessive and often deadly response to a microbial infection. Sepsis affects millions of people worldwide every year, and about half of the people with septic shock end up dying of massive organ failure. A study in Science led by Ivan Marazzi now finds that drugs that inhibit topoisomerase 1 (Top1), an enzyme best known for unwinding DNA, can protect mice from lethal bacterial infection (Rialdi et al., 2016). When pathogens invade, the innate immune system recognizes microbial molecules and turns on immune response genes that kick off an inflammatory response. The authors show that in response to microbial infection, Top1 controls the activity of RNA polymerase II at immune response genes, particularly those that require nucleosome remodeling for activation. To mimic what happens when patients are hospitalized with a viral infection and then acquire a bacterial co-infection, the authors inoculated mice with flu virus and then challenged them with a lethal dose of staph bacteria. Remarkably, when these mice were treated with a chemical inhibitor of Top1 before the staph co-infection, they were protected from death. Top1 inhibition also prevented mice injected with bacterial endotoxin from dying, suggesting a relatively broad dampening of inflammation. These findings could have potential therapeutic applications for populations most strongly at risk for sepsis, such as elderly or young patients in hospitals or other acute care environments. Another possibility would be to target mechanisms that resolve inflammation, and as it turns out, this process is also transcriptionally controlled at the chromatin level, as shown in a study from Xuetao Cao’s group demonstrating that transcriptional repression of cytokine expression by Tet2