Over the last several years, scientists have made great headway in our understanding of how self-sabotaging immune cells play a role in our ability to fight infection. So far, we know that when white blood cells called neutrophils are triggered by bacterial infection, they self-combust and eject their own DNA strands outward like spider webs. Sacrificing themselves, the exploded neutrophils and their outreaching DNA tentacles form sunburst-shaped neutrophil extracellular traps (NETs).
“NET formation is an innate immune response that our body has when it recognizes the presence of pathogens,” says Ben Croker, PhD, a researcher in the Division of Hematology/Oncology at Boston Children’s Hospital. “Once formed, NETs restrict pathogen movement and proliferation and alert the rest of the immune system to the invader’s presence.”
Now, Croker and a team of researchers at Boston Children’s have identified a critical element of NET formation and how it enables the body to fight off infections like methicillin-resistant Staphylococcus aureus (MRSA). Their findings, recently published in Science Signaling, could someday have clinical implications for tough-to-treat infections and even sepsis.
At the core of their discovery is the relationship between three genes — RIPK1, RIPK3 and MLKL — and a type of programmed cell death called necroptosis.
Cell death as a means of self-defense
In contrast to apoptosis — a normal process of cell death that keeps our body working properly and is typically ignored by our immune system — necroptosis is a type of cellular suicide that often plays a role in our immune responses. By sacrificing themselves through necroptosis, cells release their innards to their surrounding environment. This causes inflammation and signals the immune system to mount a response to infection.
Croker’s team discovered that RIPK1 primes the neutrophils for death, but does not itself determine whether they will die an apoptotic or necroptotic death. To trigger necroptosis — and ultimately, NET formation — the RIPK3 and MLKL cell death pathway must be activated.
“Understanding the pathways that lead to cell death in neutrophils is an important first-step to potential interventions that may have an impact on reducing the high mortality rates associated with sepsis,” says the study’s first author Akshay D’Cruz, PhD, who was a postdoctoral fellow in Croker’s lab at the time this research was done.
Using in vitro models of MRSA infection, Croker’s team found that mouse and human neutrophils lacking the RIPK3 and MLKL genes, or treated with drugs to block this pathway, were unable to form NETs. In contrast, cells with RIPK3 and MLKL were able to form NETs and ultimately get the MRSA infection under control.
Specifically, Croker’s team observed that the RIPK3 and MLKL genes played a critical role in activating an enzyme called PAD4, which has already been shown to be a key factor in NET release.
“This knowledge could be leveraged as a way to modulate the body’s immune response to infection,” Croker says. “In cases like MRSA infection, you may want to make these pathways more active to encourage NET formation. Alternatively, in cases where self-sacrificing cells are doing more harm than good — such as severe infection leading to septic shock — the pathway could be blocked to maintain immune cell numbers and reduce inflammation.”
Learn more about research to combat sepsis.