Pulin Li, PhD, and her lab at the Whitehead Institute in Cambridge, Massachusetts, have identified how the lungs — and other barrier organs — respond to threats on the immune system like infection. Their findings are detailed in the paper, “A Tissue-Scale Strategy for Sensing Threats in Barrier Organs,” published in Cell Systems.
Li’s team found that immune response in the lungs varies by location. Cells located deep inside the lungs’ tissue react at a more alarming rate than cells found at the outer surface, which react more cautiously.
“The central question was how tissues balance the benefits and harmful effects of immune activation when they face different degrees of danger or stress,” said Dr. Li, who is a professor of biology at Massachusetts Institute of Technology (MIT), in a news release. “Too little immune activation leaves the tissue unprotected, but too much can create inflammation and damage.”
Epithelial cells, which line the airways and air sacs of the lungs, are the first point of contact with inhaled viruses, allergens, microbes and other particles. However, the study suggests that these outermost, front-line defenders are purposefully cautious.
The researchers examined mouse models with influenza using imaging methods to measure infection and immune responses in the various cell types. Their research showed pulmonary epithelial cells were least likely to produce interferons — signaling proteins that trigger immune system responses. Meanwhile, cells located deeper in the tissue were more likely to produce interferons and alert the immune system of infection.
These findings indicate the lungs use location to determine severity of a threat, the authors noted. When infection penetrates the epithelial barrier, the lungs treat this a more dangerous and activate a stronger immune response.
“A less severe threat only requires a lower level of immune response,” said Diep Nguyen, a graduate student in the Li Lab. “As a threat goes deeper into the tissue, the inner cell types can encode that information and indicate the threat has invaded further.”
Nguyen and her colleagues identified the levels of sensitivity by tracking immune-sensing proteins called pattern recognition receptors, which detect molecular signs of infection or damage. For example, the RIG-I receptor helps cells detect viral RNA, she said. In their models, epithelial cells had lower levels of RIG-I and similar sensors, while deeper tissue cells had higher levels.
It appears the location sensitivity variance helps prevent the lungs from overreaction and prevent unnecessary damage, the scientists said. When they increased RIG-I levels in the models’ pulmonary epithelial cells, the mice produced a stronger immune response to a noninfectious threat, which increased tissue damage and obstructed repair.
“To understand the physiology, you have to take a multicellular approach,” Dr. Li said. “Thinking about tissues as communities of cells can reveal new insights into how they function.”
