Genetic disease offers new clues to skin inflammation

Pachyonychia congenita. Photo by Ali87090 via Wikimedia Commons

Pachyonychia congenita (PC) is a rare genetic disorder caused by mutations in one of five keratin genes. PC produces debilitating plantar calluses and a characteristic thickening of the nails, with no approved treatment options.

In a paper in Science Translational Medicine, University of Michigan investigators report that a single stress‑induced keratin, keratin 16 (K16), may help explain why the skin’s response to injury and stress can spiral into chronic inflammation—and how that process might be modified.

“When the skin suffers wounding and other stressors, the tissue has to figure out what to do,” said Erez Cohen, PhD, of the U‑M Medical School’s Department of Cell and Developmental Biology in a press release. “Then the question is what happens when it overreacts?”

PC shares molecular features with psoriasis and atopic dermatitis, including upregulated stress responses and immune dysregulation, but the precise functions of the PC‑associated keratins have remained obscure. The team focused on K16, a stress‑induced intermediate filament protein enriched in suprabasal epidermal layers and widely used as a biomarker in psoriasis, hidradenitis suppurativa, atopic dermatitis, and other inflammatory dermatoses.

“What we think is happening is that during inflammation or, more generally, in response to stresses, the cells making up the epidermis of the skin become activated but eventually need to come back to normal. And while we thought K16 was a driver of the activation phase, it appears to be there in part because it helps pump the brakes on that response,” said Dr. Cohen, the first author of the study.

By integrating patient plantar skin biopsies, cell culture models, and transgenic mouse systems, the researchers identified a link between K16 and type I interferon signalling, a pathway classically associated with antiviral responses. Using double‑stranded RNA to mimic viral attack, they found that complete loss or mutation of K16 amplified interferon signalling and inflammatory outputs, including heightened activation of interferon regulatory factor 7 and interferon‑stimulated gene 15 in KRT16‑null human keratinocytes.

The group then tested whether downstream blockade of this interferon signalling could mitigate the response. In a Krt16‑null mouse model of PC, topical ruxolitinib cream reduced the severity of palmoplantar keratoderma‑like lesions, suggesting a readily translatable therapeutic strategy.

“Figuring out what goes awry in rare diseases, in this case pachyonychia congenita, often has broad impact on our understanding of normal tissue physiology, disease mechanisms, and therapeutic opportunities. All too often, rare diseases are not receiving the consideration they deserve,” said Pierre Coulombe, PhD, the G. Carl Huber Professor of Developmental Biology at U-M and senior author of the study.