Researchers have now discovered that this fine balance is in part achieved by immune cells sending microRNA (miRNA) to one another.
Our immune system is constantly communicating through these small RNA molecules, but this is the first time scientists have understood exactly how miRNA messages allow for precise calibration of immune responses.
"We see the cell is sensing the infection load and then, based on that, is releasing the right amount of the right factor to shut off inflammation," said Howard Hang, PhD, the senior author and an assistant professor in the Department of Microbiology & Immunology at the University of California, San Francisco (UCSF). "This mechanism ensures that you don't have hyper-inflammation, which drives many inflammatory diseases, or hypo-inflammation, which fails to fight infection."
The researchers conducted their study in mice and a type of soil bacteria, but Hang said that the mechanisms will be the same in humans and other pathogens.
Hang's team discovered that during infection, immune cells release a swarm of miRNA-containing extracellular vesicles (EVs) that are taken up by other nearby innate immune cells—the sentries of our immune system—called macrophages and neutrophils.
The EVs' cargo of miRNA tells these immune cells how much pathogen they have encountered by delivering the miRNA messages.
In essence, the miRNA molecules measure infection load within a particular site and then spread the word to nearby immune cells, causing them to adjust their response.
"These EVs help the infected cells say to the uninfected cells, ‘Hey, we are infected. There's a lot of bad stuff here. We're making a lot of inflammatory cytokines, and you should too—but maybe not quite as much as we are,'" said Hang.
The results of the study, published in the journal Cell on October 11, 2018, have implications for understanding and treating a wide range of diseases and conditions involving the immune system, Hang said.
These include bacterial and viral infections, sepsis and other inflammatory diseases, and some cancers.
In cancer, for instance, miRNA could potentially help tumors evade immune detection, Hang said.
"What we're learning here is also about how cancer cells escape immune surveillance, perhaps by exploiting this same mechanism," said Hang.
"A cancer cell could be releasing these EVs as a way to turn down a little bit the inflammatory response, allowing the tumor to grow unnoticed by the immune system."
Hang is now studying the role of miRNA in immune cells' responses to viruses, the next step in understanding the generalizability of this mechanism.
He is also collaborating with UCSF oncologist Matthew Krummel, MD, PhD, to investigate how cancer cells manipulate miRNA to communicate and to thwart the immune system.
"This work gives us a handle on how the immune system communicates and how tumors might disrupt that communication," said Hang. "We can take this information to design new drugs and treatments to restore the proper immune response."
The research team includes members from UCSF, as well as The Jackson Laboratory and the Dana-Farber Cancer Institute.
