Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis

ABSTRACT Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. Few spontaneous animal models of esophageal eosinophilia exist, with most studies relying on artificial sensitization procedures. NF-κB-inducing kinase (NIK; MAP3K14) is a key signaling molecule of the noncanonical NF-κB (NFKB1) pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik−/− mice have been shown to develop a hypereosinophilic syndrome in peripheral blood and major filtering organs; however, the gastrointestinal mucosa of these mice has not been well characterized. We show that Nik−/− mice develop significant, localized eosinophilic esophagitis that mimics human EoE, including features such as severe eosinophil accumulation, degranulation, mucosal thickening, fibrosis and basal cell hyperplasia. The remainder of the GI tract, including the caudal stomach, small intestine and colon, in mice with active EoE are unaffected, also similar to human patients. Gene expression patterns in esophageal tissue of Nik−/− mice mimics human EoE, with thymic stromal lymphopoetin (TSLP) in particular also elevated at the protein level. In gene expression data sets from human biopsy specimens, we further show that many genes associated with noncanonical NF-κB signaling are significantly dysregulated in EoE patients, most notably a paradoxical upregulation of NIK itself with concurrent upregulation of powerful protein-level destabilizers of NIK. These findings suggest that Nik−/− mice could be useful as a spontaneous model of specific features of EoE and highlight a novel role for noncanonical NF-κB signaling in human patients.

When people think of allergies, they tend to think mostly of a runny nose or severe food allergies that lead to anaphylaxis. However, not very many people think about the mechanism underlying these symptoms. Likewise, people rarely consider other more chronic conditions, characterized by less acute symptoms that can affect the gut, especially since many of these diseases are relatively less common. My research focused on eosinophilic esophagitis (EoE), a chronic inflammatory disease that occurs in the upper gastrointestinal tract, which is basically inflammation in the throat that resembles an allergic response. Here, we identified a novel pathway that appears to impact symptoms of this disease. I found that the gene encoding a protein called NIK plays a protective role in EoE progression. Our findings show that mice that lack NIK develop an inflammatory disease of the esophagus, similar to human EoE, and that NIK may have importance in many cell types associated with the disease process.
What are the potential implications of these results for your field of research?
EoE is a relatively understudied disease. Thus, the model we describe in our recent work may be highly useful in evaluating new therapeutics and for further defining the mechanism/s underlying the disease in human patients. Likewise, the gene we have identified that encodes NIK has not been broadly characterized and it may also present a new therapeutic target that can affect both the immune system and the epithelial cells that line the esophagus. It was exciting to make a connection between a loss or disruption of NIK and a disease with human implications, as dyregulation of the pathway controlled by NIK has not been previously explored in eosinophilic diseases of the upper gastrointestinal system.

What has surprised you the most while conducting your research?
We were surprised to find this disease in our mice, given that our previous experience looking at the lower GI tract did not show the same phenotype. It was also surprising how localized the phenotype is, similar to the human EoE. We were not expecting to see such a targeted GI phenotype.
What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating?
and correlate these findings between the mouse and human. The global knockout animals used here are an informative stepping stone for determining the more specific effects of target genessort of like taking a large part out of a machine and then adding small pieces back bit by bit to determine the most essential cogs. "Proper mentoring is absolutely essential in early career development for scientists, and particularly career-oriented mentoring such as coaching for job searches and grant applications." Describe what you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
I believe a significant challenge is the communication of people from various backgrounds and fields into projects. Of course, interdisciplinary research with varied faculty is highly sought after and encouraged, but there are of course always problems with communication, experience, and overall goals. As a veterinary pathologist, I need to make my experience and language accessible to basic science researchers, who in turn must be able to communicate with clinicians and ultimately patients. Multicomponent teams can be intensely efficient at creating data, but we must also be able to make sure our data is understood not only within our own groups, but with the downstream recipients of our work; including other scientists, doctors, and the general public.

What changes do you think could improve the professional lives of early-career scientists?
Proper mentoring is absolutely essential in early career development for scientists, and particularly career-oriented mentoring such as coaching for job searches and grant applications. Both of these processes are stumbling blocks, yet are critical for the success of investigators as they move towards independence.

What's next for you?
I'm relatively open with my career options. I would like to remain in academia, but have also developed an interest in both government and industry. As a DVM, and soon to be PhD, there are several opportunities for me in each sector and I look forward to exploring my options.