A groundbreaking discovery is reshaping our understanding of skin inflammation! Dr. Michael Rosenblum's team has uncovered a previously underestimated group of fibroblasts that actively control inflammation, fibrosis (scarring), and how our skin deals with microbes. This could revolutionize how we approach skin diseases.
At the 2025 Inflammatory Skin Disease Summit, Dr. Rosenblum, a dermatology professor at UCSF, shared insights from over a decade of research. He began by reflecting on how much the field has evolved, particularly concerning regulatory T cells (Tregs). He noted, "I used to need several slides to explain these cells, but now, thanks to the Nobel Prize… everyone seems to know about Tregs." His presentation journeyed from the basics of immune cell development to the intricacies of stromal cell biology, ultimately leading to early clues about human diseases.
Rosenblum highlighted that most Tregs are found in peripheral tissues, not the typical immune hubs. As he explained, "The skin and GI tract actually have the vast majority of Tregs in the body," suggesting their roles extend beyond simply suppressing the immune system. His lab's research over the last 15 years has shown that Tregs are deeply involved in normal skin functions. They help hair follicles cycle, promote skin repair, manage fibroblast activity and fibrosis, and protect hair follicle stem cells from immune attacks. This research paints Tregs as essential for maintaining healthy skin, not just as inflammation controllers.
A key part of the presentation focused on the discovery of what Rosenblum's group calls the neonatal "Treg wave." In mice, Tregs flood the skin between 6 and 13 days after birth, increasing "from about 20% of the CD4 compartment to over 80%." This surge happens alongside hair follicle development, initial environmental exposures, and rapid skin maturation. The team theorized that this Treg wave is crucial for "immune imprinting," an early-life process that may determine a person's susceptibility to inflammatory conditions later on.
To test this, Ian Boothby, a student, used special mice to remove Tregs during this neonatal period. While the mice appeared normal, their skin told a different story. Boothby observed an unusual fibroblast population forming fibrotic strands within the subcutaneous fat, along with inflammation and a stable Th2-rich immune environment. These fibroblasts, initially called TIFFs (Th2-interacting fascial fibroblasts), seemed to create a self-supporting niche with Th2 cells. And this is the part most people miss: This short-term neonatal disruption of Tregs could reprogram the skin's structure and immune system well into adulthood, raising important questions about the early-life origins of skin diseases.
The group then set out to better understand these fibroblasts. Single-cell RNA sequencing revealed a distinct cluster defined by high levels of the IL-13 receptor α1 subunit and other markers. Translating these genetic signatures into physical traits, the researchers identified the cells as CD26^high CD29⁺ fibroblasts located along the fascial plane. Their genetic profile closely matched a fibroblast population described by Shannon Turley's group, known as PI16-positive universal fibroblasts, suggesting that Rosenblum's TIFFs were part of a widely conserved stromal lineage.
To aid their studies, the lab created an inducible PI16-CreERT2 mouse, allowing them to track, eliminate, or modify genes within this fibroblast group. Rosenblum jokingly said that “once you have a hammer… the whole world then becomes a nail,” highlighting how essential this tool has become.
Postdoctoral fellow Max Kinay used this system to study the role of PI16-positive fibroblasts in bleomycin-induced skin fibrosis. Surprisingly, removing these fibroblasts didn't reduce fibrosis; instead, it increased collagen deposition. Rosenblum noted, "It was the exact opposite result," a finding they repeatedly confirmed. This means these fibroblasts act as regulatory fibroblasts that prevent, rather than promote, pathological scarring. The team is now working to identify the specific molecular pathways these cells use to restrain fibrosis.
Another postdoctoral fellow, Hitoshi Terui, investigated whether PI16-positive fibroblasts contribute to abscess formation. By infecting reporter mice with Staphylococcus aureus, he found that these fibroblasts quickly surrounded bacterial infections, forming the fibrotic wall of an abscess. When the fibroblasts were removed, abscesses grew larger, and bacteria spread to organs like the spleen and kidney. These observations suggest that PI16-positive fibroblasts are crucial for containing pathogens and preventing systemic infections.
Rosenblum then discussed the implications of this work for humans. Using cross-species analysis, his team mapped the mouse TIFF/PI16 genetic signature onto human single-cell datasets and found a clear counterpart in normal human skin. Initial patient studies focused on eosinophilic fasciitis (EF) because its pathology—fibrotic bands in subcutaneous fat and a type 2 immune response—resembled their neonatal Treg-depletion model. In an untreated EF patient, PI16-like fibroblasts were increased, and Th2 cells were found in the same fascial regions, supporting the idea of a fibroblast–Th2 axis contributing to the disease. The team is now recruiting more patients with EF, morphea, and other fibrotic conditions.
In closing, Rosenblum proposed a new name: "I propose that we call these cells… PI16-expressing fibroblasts, or PIFs," a name that reflects both their molecular identity and broad functional roles. His presentation highlighted a paradigm shift: fibroblasts are not just passive structural elements but active regulators of immune tone, fibrosis, and microbial containment. For clinicians, these findings suggest a new fibroblast–immune axis that could shape future treatments for inflammatory and fibrotic skin diseases.
But here's where it gets controversial... This research challenges the traditional view of fibroblasts and opens up new avenues for treating complex skin conditions.
What do you think? Does this new understanding of fibroblasts change how you view skin inflammation and disease? Share your thoughts in the comments below!
