What KLK5 Taught Me About Atopic Dermatitis

Research By: Nurit Azouz, PhD

Post Date: October 28, 2026 | Publish Date: September 18, 2026

Post authored by Nurit Azouz, PhD
Assistant Professor: Pediatrics, Allergy and Immunology
Cincinnati Children’s Hospital Medical Center and
University of Cincinnati College of Medicine

In science, some of the most interesting discoveries begin with a result that contradicts our hypothesis.

For years, researchers have known that the enzyme kallikrein 5 (KLK5) is involved in skin inflammation. KLK5 is an extracellular serine protease that is highly expressed in the skin. Increased KLK5 activity has been linked to inflammatory skin diseases, including atopic dermatitis and Netherton syndrome. From these observations, it would be reasonable to assume that eliminating KLK5 might protect against allergic skin inflammation. Instead, our team discovered the opposite.

In our recent study published in Mucosal Immunology, we found that the complete loss of KLK5 worsens allergic skin disease in mice, revealing a previously unrecognized protective role for this enzyme.

A Surprising Result

Because excessive KLK5 activity has been linked to skin inflammation and barrier dysfunction, we asked a different question: What happens when KLK5 is completely absent?

To find out, we used two mouse models of atopic dermatitis and compared mice lacking KLK5 to controls. We expected KLK5 deficiency to reduce inflammation. Instead, mice lacking KLK5 developed more severe disease, including increased inflammation and scratching behavior.

These findings were particularly unexpected for me because my research has long focused on the role of proteases in allergic diseases. Previously, I investigated the function of KLK5 in the esophageal epithelium during eosinophilic esophagitis (EoE), another allergic disorder characterized by epithelial barrier dysfunction. In contrast to our findings in the skin, deletion of KLK5 was protective in experimental EoE. These contrasting findings underscore how the same molecule can have distinct roles in different tissues and diseases.

Connecting the Skin Barrier and the Immune System

One of the most intriguing findings involved filaggrin, a key structural protein that helps maintain the skin barrier. Mice lacking KLK5 had impaired processing of filaggrin and reduced levels of mature filaggrin, suggesting that the worsening inflammation may begin with barrier dysfunction rather than the immune system itself.

When the barrier is compromised, allergens, microbes, and environmental irritants can more readily penetrate the epidermis and interact with immune cells. Consistent with this possibility, KLK5-deficient mice accumulated increased numbers of Langerhans cells, specialized antigen-presenting cells that help initiate immune responses. We also observed significant changes in the skin microbiome and the microbial metabolism in mice lacking KLK5.

Together, these findings suggest that KLK5 may contribute to skin health beyond maintaining the physical barrier alone. The changes we observed in filaggrin processing, immune cell accumulation and the skin microbiome highlight the intricate nature of barrier function, microbial communities, and immune responses, adding to growing evidence that maintaining a healthy skin ecosystem is critical for preventing allergic disease.

Can Barrier Repair Reverse Disease?

Our findings also raised another question: Was the worsening inflammation simply associated with barrier dysfunction, or was barrier dysfunction actually helping drive the disease?

To explore that possibility, we treated mice with cis-urocanic acid, a naturally occurring molecule produced during filaggrin processing. The treatment significantly reduced inflammation, supporting the idea that impaired barrier function is a key mechanism underlying the worsened disease in the absence of KLK5.

Though more work remains, these results suggest that restoring barrier function may be just as important as suppressing inflammation itself.

Why This Matters

One of the key lessons from biomedical research is that biology rarely follows simple rules. Molecules that drive disease under some conditions may be protective under others.

Our study demonstrates that both excessive KLK5 activity and complete loss of KLK5 can be detrimental in the skin, suggesting that maintaining the proper balance is essential. More broadly, the findings highlight the close relationships among epithelial barrier biology, microbial communities and the immune system.

This project reinforced one of my favorite aspects of scientific research: the most meaningful discoveries often emerge when the data challenge our expectations.

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Publication Information

Original title:	Loss of kallikrein 5 expression exacerbates allergic skin inflammation including impairing filaggrin processing, promoting Th2 differentiation and inducing dysbiosis
Published in:	Mucosal Immunology
Publish date:	September 18, 2026

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