SPINK7 Deficiency Unleashes Inflammatory Cascade in EoE

Published June 6, 2018 | Science Translational Medicine

Scientists have known for some time that the allergic inflammatory responses seen among people with eosinophilic esophagitis (EoE) are connected to impaired function of the epithelial barrier within the esophagus. Now, a research team has tracked down one of the molecular culprits involved.

The study, led by Nurit Azouz, PhD, and Marc Rothenberg, MD, PhD, reports that a deficiency in the serine peptidase inhibitor kazal type 7 (SPINK7), along with uncontrolled protease activity, plays a causative role in compromising the esophageal barrier. 

“We suggest that SPINK7 represents a novel checkpoint in regulating innate immunity, and its deficiency,” the co-authors say.

The team found that loss of SPINK7 expression caused a defect in epithelial cell differentiation, reduced expression of barrier proteins including filaggrin, impaired epithelial barrier function, and unleashed the production of a set of pro-inflammatory mediators including thymic stromal lymphopoietin (TSLP), IL-8, GM-CSF and CCL2.

Mechanistically, SPINK7 inhibited urokinase plasminogen activator (uPA) and kallikrein 5 (KLK5). Translational studies revealed increased uPA activity in the esophagus of EoE patients and dynamic modulation of the uPA receptor by esophageal eosinophils.

Genetic studies revealed a strong epistasis between genetic variants in PLAU (gene product, uPA) with the atopy risk variant in TSLP gene.

“We propose that SPINK7 deficiency and uncontrolled protease activity serve a causative role in compromising the esophageal barrier,” the co-authors wrote.

Additionally, EoE disease susceptibility is influenced by genetic interactions between variants in this pathway (SPINK7 and PLAU) and cardinal atopy pathways (ST2 and TSLP).

An image depicting and EoE patient with food dysphagia.

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An image of epithelium with eosinophilic esophagitis.

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A photo of Nurit Azouz, PhD.

Nurit Azouz, PhD

A photo of Marc Rothenberg, MD, PhD.

Marc Rothenberg, MD, PhD

Citation

Azouz NP, Ynga-Durand MA, Caldwell JM, Jain A, Rochman M, Fischesser DM, Ray LM, Bedard MC, Mingler MK, Forney C, Eilerman M, Kuhl JT, He H, Biagini Myers JM, Mukkada VA, Putnam PE, Khurana Hershey GK, Kottyan LC, Wen T, Martin LJ, Rothenberg ME. The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses. Sci Transl Med. 2018 Jun 6;10(444).