By Isabella Cueto July 22, 2022
An illustration of Cutibacterium acnes, sebum-loving bacteria involved in the formation of acne lesions. ADOBE
Cutibacterium acnes, a crunchy Cheeto-shaped bug that lives on human skin, loves the oily pocket around hair follicles. No face is quite as greasy as that of adolescents, flooded with hormones that grow hair, deepen voices, and ramp up production of sebum, a secretion that makes the skin a moist and protective barrier.
Too little sebum means dry, flaky skin, like patches of eczema. Too much sebum means acne, the skin disease caused by C. acnes. Bumps and zits and blackheads sprout on most teenagers and, increasingly, on the faces of young adults, even into their 20s and 30s. And, in people with extra-oily skin, the body’s natural defenses can’t seem to get rid of the bacteria.
A new study in Science Immunology gives clues as to why more than 45 million people have acne, a disease that has been shown to be psychologically and socially devastating for young people. Led by Robert Modlin, the Klein Professor of Dermatology at UCLA, a team of researchers found overzealous and underperforming immune cells.
Macrophages are one of our immune system’s first responders. They rush to the site of a problem, and are commanded to clean up, take away dead cells, and get rid of pathogens and other unwanted tidbits. When it comes to acne-prone skin, macrophages are called in to soak up the extra oils – lipids – and kill the bacteria that lead to clogged pores and inflammation (that big red bump on a friend’s forehead). But something about the oil, a component of sebum called squalene, is transforming what should be a garbage truck into a reservoir for C. acnes bacteria to grow. The Modlin lab studied skin from the backs of six people – nearly 33,000 cells from day-old acne lesions and 29,000 cells from non-lesional skin – and simulated acne lesions in Petri dishes to find a potential answer.
After analyzing genetic sequencing, Tran Do, an M.D.-Ph.D. student and lead author of the paper, had the idea to put squalene directly into the dish with the regular macrophages. What emerged were these mysterious, “foamy” macrophages, called Trem2 macrophages, that Do later found mentioned in papers about other fat-related chronic diseases.
The Trem2 macrophages were clustered around oily hair follicles, acting like nightmare party guests. They would get to work, and stuff themselves by guzzling as much oil as they could, but were “overly optimistic at the lipid buffet,” Modlin said. Instead of defeating C. acnes, the macrophages were stripped of their infection-fighting powers (though it’s still unclear how). One tactic: the squalene in a foamy macrophage’s belly finds oxygen radicals – molecules that can kill acne bacteria – and incorporates them into its oily stew, neutralizing the threat, letting acne flourish.
“This acne bacteria is specialized to live there,” said Modlin, who is also a professor of microbiology, immunology, and molecular genetics at UCLA. “It utilizes the lipids from that environment to grow, and it also has worked with the host to avoid getting killed.”
The research, published Friday, helps explain on a more granular level why benzoyl peroxide, a popular but irritating first-line treatment for acne, works. What the Trem2 macrophages can’t accomplish, benzoyl peroxide can: overcoming the squalene’s oxygen radical-absorbing trick to kill acne bacteria. Finding out more about a particular pathway that leads to acne can open the door to more treatments, or to understanding why certain treatments, like the powerful drug Accutane, are so effective at curing acne, said Alvin Coda, a dermatologist at Scripps Clinic in La Jolla, Calif.
“You can have 10 different medications with 10 different targets to treat one disease,” Coda said, because skin illnesses are so complex, with inflammation being driven by multiple, intricate processes. The American Academy of Dermatology’s acne guidelines suggest the best approach is to reduce sebum production, open up pores, and reduce inflammation. While research has asserted since the late 19th century that C. acnes are involved in the formation of acne lesions, scientists are still investigating exactly how and why acne happens. Most agree that it is a multifactorial disease, and no single cause is to blame.
Figuring out how lipid gums up the body’s immune reaction also has larger implications, Modlin said. He found his way to acne research from leprosy (Hansen’s disease), his main area of study, because the two diseases share a genetically similar bacterial infection. In some forms of leprosy, foamy macrophages can harbor hundreds of bacteria in each cell — an extreme version of what occurs in acne patients. “Your pimples go away in two or three days, so eventually you win over the bacteria,” he said. In severe leprosy, “the bacteria wins.”
But numerous other conditions, including some forms of non-alcoholic fatty liver disease, obesity, Alzheimer’s disease, certain cancers, foam cell tuberculosis, and atherosclerosis, could be driven by “likely identical” foamy, Trem2 macrophages.
In Alzheimer’s, there is an increase in Trem2-expressing macrophages – microglia – scooping up lipids in the brain. In nonalcoholic steatohepatitis (fatty liver disease), researchers have found more Trem2 macrophages in the liver. These macrophages are also increased in many cancers, Harmeet Malhi, a consultant in the Mayo Clinic Division of Gastroenterology and Hepatology, told STAT in an email. “Another interesting observation is that the age distribution of the three conditions does not have significant overlap, suggesting that these lipid response macrophages can be implicated in diseases across the lifespan,” she said.
What scientists glean from inside pimples could eventually lead to the development of more targeted acne treatments, and help advance the understanding of other lipid-related chronic conditions, too.
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