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Benzoyl Peroxide Is the Best Topical Acne Medicine, Immune Pathway Shows

photo of woman applying acne cream to cheek
Benzoyl peroxide helps overcome squalene's effect on immune cells attacking acne bacteria. | Photo courtesy of Medical News Today

Acne has a reputation as a condition specific to teenagers in the throes of puberty. Yet for many people, the disease is long-lasting, disfiguring, and socially isolating.

Now, a Science Immunology study by Robert Modlin, a professor of dermatology and microbiology, immunology, and molecular genetics at University of California, Los Angeles, and his colleagues reveals how some immune cells interact with oil in the skin and acne-causing bacteria to contribute to this widespread skin condition. The results indicate one of the best treatments for acne is the readily available topical medicine, benzoyl peroxide.

In the past two years, dermatologists have noticed that the number of those with chronic acne is growing. But while acne is experienced by roughly 10% of people worldwide, it hasn't received as much attention or funding in the scientific sphere.

"It really has been understudied," said Modlin, the paper's corresponding author. "I've had comments such as 'it's cosmetic,' and yet, it is a serious disease. There are many studies about depression, suicide rates, difficulty with employment, and [poor] sense of well-being."

Foamy Immune Cells

To investigate the relationship between the immune system and acne, Modlin and colleagues performed single-cell RNA sequencing and other types of analyses on roughly 32,966 cells in early-acne lesion biopsies from six patients with acne. In doing so, they observed a unique group of macrophages, or white blood cells, which rush to sites of infection to engulf intruders.

The macrophages were expressing a protein marker called "TREM2" and looked foamy. The scientists compared how common the foamy cells were in biopsies of lesions versus in biopsies of skin without acne, finding that 95% of the macrophages came from acne samples. This signaled to the team that something unusual must be happening in the lesions.

"One of the cells I noticed that also had differences between lesional and nonlesional samples was keratinocytes, which were producing a lot of lipids. The keratinocytes in lesions were also localized in same area as the TREM2 macrophages," said Tran Do, the study's first author and a future resident at the University of Michigan dermatology program. "That's how we put the story together. These macrophages are responding to the lipids and the lipids are coming from these hair follicular cells, which are linked to sebum production."

diagram of research on immune interactions in acne
Newly discovered immune pathway shows how acne bacteria, lipids and immune cells interact spatially in skin. | Do et al., Sci. Immunol. 7, eabo2787

As the researchers explored further, they realized that there was one particularly abundant lipid that might be impairing the macrophages' ability to effectively kill the acne-causing bacteria, Cutibacterium acnes (C. acnes). That lipid was squalene.

Scavenging Lipids and an Existing Drug

Produced by flora and fauna, squalene was first identified in the late 1910s as an organic compound in shark liver oil. Nowadays, the substance is sometimes used an ingredient in vaccines for elderly people to help enhance their immune response to pathogens.

But in this instance, squalene was actually blocking an immune response. Macrophages use a type of chemical reaction called oxidation to kill bacteria on the skin. The process relies on free oxygen radicals, unstable molecules that have oxygen in them. Meanwhile, squalene and its derivatives are antioxidants, meaning they can inhibit oxidative processes.

"Squalene acts as a scavenger to take up those oxygen radicals. That suggested that blocking the squalene synthesis pathway could be a target," said Modlin. "After that, it didn't take long to realize that one of the best treatments for acne is benzoyl peroxide."

Since the drug is an oxidizing chemical, it can be harnessed to kill acne-causing bacteria when TREM2 macrophages cannot. This is important because many existing acne medications stimulate cell turnover and unblocking pores. Although those treatments may also support the immune system, how they do so is less clear. The new research distinctly shows benzoyl peroxide can target C. acnes, a key trigger in the acne cycle.

While the study highlights benzoyl peroxide's utility against acne, Modlin stresses that another equally valuable takeaway of this work is that it spotlights acne as a serious disease and presents a foundation for studying how lipids and macrophages interact in other skin conditions.

Moving forward, the team hopes to see more research that comprehensively examines the skin by analyzing local cells' genetic material and the microbiome in which they operate.

"It really opens the field up to thinking how the skin environment influences the types of immune cells present and how those interactions trigger certain diseases," said Do.