The Immune System’s Weirdest Weapon
Every drop of pus that’s squeezed out of the human body is a squidgy mess—a souvenir of an infection gone awry, a reminder to never eat off-color custard again. It is also a wartime memorial, dedicated to the corpses of the many thousands of microscopic soldiers that once teemed within. The fallen are neutrophils: stalwart immune cells that throng in the blood by the mind-boggling billions, waiting to rush to sites of injury or infection as a first line of defense.
Maybe it’s their short life span; maybe it’s the fact that they’re the main ingredient in pus. For whatever reason, neutrophils have a history of being slandered as inessential grunts. They are by far the most abundant white cells in the blood, among the first immune cells to sally forth into battle, and among the first to perish in the fight that follows. They are, by definition, dispensable, replaceable, and almost absurdly common, noted more by biologists for their propensity to die than for the roles they play in keeping us alive.
But that’s a regrettable miscasting of a superpowered cell. Neutrophils are more Cylons than stormtroopers. While other immune cells creep by at speeds of just a couple micrometers per minute, neutrophils can barrel through vessels 10 times as fast, and are flexible enough to squeeze themselves through spaces that span less than an eighth of their width. They are healers that can help stitch torn tissues back together; they can wrangle tumors too, and shape the fate of the immune cells that follow them.
Neutrophils also harbor one of the immune system’s most terrifying armaments: They can unspool the genetic material that’s normally packed into a tight wad at their center, freckle it with toxic proteins and compounds, and then spew it out their side like a lethal sneeze—a weaponization of their own DNA. The end product is a gummy, poisonous net called a neutrophil extracellular trap, or NET, that can massacre scores of microbes at once. But NETs are a double-edged sword: When cast under the wrong circumstances, they can harm their host, seeding serious blood clots or driving the symptoms of diseases as catastrophic as cancer, lupus, and COVID-19. Researchers around the world, scientifically snared by NETs, are now pouring resources into stopping them, and turning rogue neutrophils back onto our side.
Pus is a disgusting placard, but a useful one. It trumpets to the world that neutrophils were here. And they were absolutely metal.
Neutrophils should, by now, be a notorious bunch. Perhaps some of their biological clout has been obscured by their allegiance to the innate immune system, the oft-neglected branch of the body’s disease-stomping military that’s speedy, blunt, and rather imprecise. Unlike adaptive actors such as antibodies and T cells—which can remember past encounters with pathogens and repeatedly refine their defensive tactics—innate cells indiscriminately clobber anything in their vicinity that they don’t recognize, earning them a reputation among scientists as brainless brawn.
Even among the innaters, neutrophils have often been portrayed in textbooks as being particularly hapless: cells that rush headlong into sites of infection or injury, only to extinguish en masse before much of the real fighting—the war waged by more “sophisticated” cells—could actually begin. For decades, researchers would even claim that neutrophils didn’t count as classically immune. “Nobody thought they were interesting,” Denisa Wagner, an immunologist at Harvard who has been studying neutrophils for decades, told me. “Everybody was looking at antibodies, all this stuff that sounds sexy.” Neutrophils, by comparison, seemed a woefully boring bunch. To make things worse, they can’t be bred in labs, and must be collected fresh from blood or other bodily fluids every time they’re studied, making researchers loath to experiment with them.
The few scientists who did take up the inglorious mantle, however, quickly found a wealth of lore to uncover. Anna Huttenlocher, a rheumatologist at the University of Wisconsin at Madison, has spent years watching the cells zoom through tissues and built structures in the lab. They are, as she describes them, capable of remarkably elegant acrobatics, earning them verbiage as delightful as “rolling” and “tumbling” as they cavort through the blood. Neutrophils, Huttenlocher told me, are fast, flexible, and accurate when they travel, beating other cells to the punch, then entering the spaces that their comrades in arms cannot. “They are the best migrators in your body,” she said.
Old chapters on neutrophil combat are even being rewritten to account for the cells’ pluck and aplomb. Once they’ve hit their destination, neutrophils beam frantic signals out to thousands and thousands of their comrades, until they’ve recruited enough to flood the compromised tissue in a furious, pulsating swarm. This works best against a pathogen such as a bacterium, which neutrophils can waylay outside of cells; within minutes of an invasion, the horde will begin gobbling up its opponents and tossing noxious, microbe-killing grenades into the fray. The goal is containment. “Every hour that you can keep an infection from spreading to the whole organism is a good thing,” Christian Con Yost, a neonatologist and neutrophil biologist at the University of Utah, told me. “They’re doing what they can to wall it off.”
The carnage of these clashes can be staggering: Most neutrophils are thought to die just hours after being born in the bone marrow, either at the hands of a microbe or from detonating their own DIY bombs. But this narrative is overly simplistic. Many neutrophils survive their first foray into battle, and see no reason to snuff themselves out on site. “You don’t actually want a lot of cells dying in tissue,” Huttenlocher told me, a process that can leave behind a sloppy and potentially inflammatory mess.
Paul Kubes, an immunologist at the University of Calgary, in Canada, and his colleagues are trying to catalog the places that neutrophils go to die. Many seem to trek out to other tissues in need, or bunker down in the immune-cell depot of the spleen; others are extruded as bodily waste, or will even return to their home base—the bone marrow—to be recycled into a new generation of defensive cells. Mapping out these graveyards and when and why they’re used, Kubes told me, could help scientists suss out how long the cells can last. “This is probably the most controversial area right now,” Kubes said. “We’re finding them in all kinds of different places, living for much longer than we thought.”
All neutrophils must die. But they can leave behind a trail of hazardous debris and unexploded ordnance. Their lethal NETs, in particular, appear to be a tactical last hurrah for cells that are outmatched by microbes, or are out of other weapons, Kim Martinod, an immunologist at KU Leuven, in Belgium, told me. “You would want to have some mechanism to still try to, as a last resort, contain the pathogens.” NETs are potent and persistent enough to keep the fight going even after the warrior is dead, like land mines strewn across a battlefield.
Microbes that get caught by NETs find themselves as doomed as insects in a spider’s silken web: If they’re not immediately gutted by the lethal molecules that stud the sticky structure, they’ll at least be immobilized, smorgasbord-style, “until other immune cells come and eat them,” Shuichi Takayama, a biomedical engineer who’s building artificial NETs in his lab at Georgia Tech, told me. “They’re really like cellular Spider-Mans.” (NETs also show up in our pus, which is grodier when it’s NETtier, and far more interesting for it.)
NET release can mean instant death for the neutrophil. But in a macabre twist, Kubes and others have found that some cells can delay their demise, perhaps for hours after they blow. After jettisoning their genetic blueprints, certain neutrophils will shamble onward, still trying to slurp up stray microbes that their web didn’t catch. “They crawl around like zombies,” Rachel Kratofil, one of Kubes’s graduate students, told me. Many of the details that dictate which neutrophils go undead are still murky. Some researchers think certain cells might be able to expel just fractions of their DNA and retain the rest, though exactly how choosy they can be is unclear.
The repercussions of NETs are wide-reaching, in ways good and bad. On one hand, the traps can completely alter the course of a growing infection, work by Kubes’s team has shown, stoppering a surge of bacteria that might have otherwise slipped by. On the other hand, NETs are chaotic cascades, easy to fling and impossible to reel back in. Once a NET is tossed, it’s tossed: It can’t discriminate what it catches, be it microbial or human, dangerous or benign, Nades Palaniyar, a neutrophil biologist at the University of Toronto, in Canada, told me. The NET’s toxic proteins can gnaw away at the fragile architecture that holds blood vessels together, while its sticky surface quickly attracts and gums down platelets, the perfect scaffold for clots. The destruction then marshals even more immune cells to the fore; a vicious cycle begins.
Many scientists, including Martinod in Belgium, are investigating NETs that form in organs and blood vessels—places where neutrophils might be drawn in by damage, even if there are no microbes to be found. Wayward NETs are now known to affect the pancreas, lungs, brain, and kidneys; they’re also being implicated in viral illnesses such as COVID-19, in which blood clots run rampant. Severe coronavirus infections, Martinod told me, “are kind of this perfect storm for NET release … they’re formed in the lung, but also systemically.” Stray shreds of neutrophil DNA can also attract antibodies, fueling autoimmune conditions such as lupus. NETs can even shield cancerous cells from other members of the immune system, or egg them on as they grow.
NETs “are so beautiful,” Martinod told me. “I spend most of my time trying to keep them from happening.” Executing that reality, though, isn’t trivial. Neutrophils, after all, are among the body’s most essential cells. “If you don’t have neutrophils, you can die from infection within 24 to 72 hours,” Kratofil told me. The goal, then, is to nullify NETs without obliterating the cells that wield them. Some researchers are trying this tactic against COVID-19 by chopping up NETs that have already formed, using potent molecules that can shear through strands of DNA. But Martinod worries about this approach: “If you break them into smaller pieces, you allow them to circulate.” Another option, Kubes said, could be to muzzle neutrophils so that they don’t deploy their genetic ammunition at all, like permanently flipping the safety on a gun. But that’s likely a trickier treatment to perfect.
Neutrophils are no ninnies. They have evolved to be problem solvers—sweeping up pathogens and scarfing them down, repairing wounds and paving paths for new tissues to grow. Their substantial capabilities create substantial dangers for the host, but also an enormous potential to be harnessed for good. If the cells can aggravate tumors, for instance, perhaps they can tame them as well. A neutrophil isn’t some foot soldier destined to be mummified in pus. It’s a heavily armed commando, to be deployed with care. It’s a NET-slinging super-soldier, whose true potential may still be untapped.