Atopic dermatitis development is influenced by “loss of IKKB function,” researchers observe
10 Mar 2022 --- Atopic dermatitis is an inflammatory disease caused by a breakdown in the skin’s barrier function. The nuclear factor kappa-B (NF-kB), a master regulator of inflammatory reactions was found to impact the emergence of atopic dermatitis as it influences skin inflammation.
This is according to researchers from the University of Pennsylvania and Oak Ridge National Laboratory, US, who created a mouse model that lacked IKKB, an NF-kB signaling activator.
“The study indicates that the loss of IKKB function in a specific subset of skin fibroblasts that impairs NfkB signaling may predispose some individuals to skin inflammation that mimics atopic dermatitis,” John Seykora, professor at the departments of Dermatology and Pathology, University of Pennsylvania tells PersonalCareInsights.
“This study broadens the potential cellular targets for treating atopic dermatitis to include skin fibroblasts and dermatologists should now think about whether they need to be targeting fibroblasts when treating this skin disorder.”
Identifying inflammatory signaling
Identifying inflammatory signaling before skin ulcers emerge has given insight into the condition’s early stages and identified potential new molecular targets for therapeutic intervention.
The researchers found that as the mice that lacked IKKB grew older they acquired skin lesions.
The findings lead to a new approach to therapy development for atopic dermatitis.
Also known as eotaxin, CCL11 is a signaling molecule that promotes inflammation by recruiting a class of white blood cells called eosinophils to its location.
“An interesting finding of the study is that eosinophil recruitment may set the stage for an allergic immune response. This is the opposite of what is typically expected,” Dana Graves, professor, department of Periodontics, University of Pennsylvania, also tells PersonalCareInsights.
Inflammation during dermatitis development
“By using mice with a targeted deletion, we followed the initial development and progression of skin lesions that are difficult to establish in humans,” says Graves.
The researchers noticed skin thickening and infiltration of certain types of white blood cells, both of which are common in human atopic dermatitis.
To learn more about how IKKB depletion caused these effects, the researchers used single-celled RNA analysis, a technique that determines which RNA transcripts are present in individual cells.
The scientists observed that fibroblasts, a fundamental component of the skin’s dermis layer and normally assumed to support skin’s structural integrity, were responsible for these impacts.
“The study in mice suggests several steps in atopic dermatitis that need to be investigated in very early human skin lesions including changes in fibroblasts and early-stage eosinophil recruitment and whether they precede the formation of a typical Th2 allergic inflammatory response,” adds Graves.
The researchers plan to use analytic approaches to extend these findings in human atopic dermatitis samples.
“Skin fibroblasts traditionally have been thought of as producers of extracellular matrix molecules – collagen, elastin and hyaluronic acid – that give skin its appearance. Our study and other recent studies indicate that fibroblasts play key roles in regulating inflammatory reactions in the skin,” adds Seykora.
Decreasing NF-kB activity
Although NF-kB commonly promotes inflammation, this study’s decreasing NF-kB activity led to immune cell recruitment and inflammation.
The research team’s single-cell RNA analysis revealed that in the fibroblasts lacking IKKB, a protein transcription factor termed CEBPB was highly activated. In these fibroblasts, CCL11 was also very active.
When the researchers compared their findings in mouse cells to skin samples from humans with atopic dermatitis, they discovered similar patterns: CCL11 and CEBPB were identified at higher levels in affected skin than in unaffected skin.
They also used an inhibitor of IKKB to conduct parallel tests in human skin fibroblasts and found that CCL11 levels increased substantially.
Returning to the mouse model, the researchers discovered that administering a monoclonal antibody against CCL11 suppressed the inflammatory response seen in animals lacking IKKB, implying that this route could be one to target to reduce atopic dermatitis-related inflammation.
“The next steps are to extend the original observations in the dermal fibroblasts to understand better how the IKKB/NfkB/CEBPB/CCL11 is regulated in the murine model and human atopic dermatitis samples,” says Seykora.
By Nicole Kerr
