Suppression of Hippo Pathway by Food Allergen Exacerbates Intestinal Epithelia Instability and Facilitates Hypersensitivity

Abstract

Scope Hippo signaling is a crucial pathway in innate immune responses, but the relationship between food allergy and Hippo pathway is unknown. The aim of this work is to investigate the regulation of food allergy by Hippo pathway and reveal the molecular mechanisms. Methods and results Two food allergens tropomyosin and ovalbumin are used to challenge a mouse model and CMT93 intestinal epithelia cell model. The allergic responses and the activation of Hippo pathway are tested in these models. In the mouse model, both allergens trigged significant allergic responses, and Hippo pathway is suppressed after allergen challenge. In CMT93, both allergens upregulate the expression of allergic cytokines thymic stromal lymphopoietin, interleukin (IL)‐25, and IL‐33. In TAZ KD CMT93, the Hippo pathway is blocked, and the expression of allergenic cytokines are also suppressed. Conclusions Both in vivo and in vitro data demonstrate that the two food allergens suppressed Hippo pathway by downregulating TAZ expression, resulting in intestinal epithelia instability, and finally leading to hypersensitivity reactions. These findings provide potential therapeutic targets and molecular markers for food allergy, and provide dietary guidelines for allergenic individuals.

An advanced in vitro human mucosal immune model to predict food sensitizing allergenicity risk: A proof of concept using ovalbumin as model allergen

“…Therefore, a growing body of research is focusing on the development of advanced in vitro mucosal immune models to allow effective safety and allergenicity risk assessment of novel food proteins and to provide tools for further mechanistic studies without the use of animal models ( 10 ). Recent attempts have aimed to develop sensitizing allergenicity models up till the T cell response ( 11 , 12 ), however the use of murine cells may lack translational value to study food allergy from a human perspective. In a similar approach we recently showed the contribution of epithelial cells in driving the first steps of allergic sensitization ( 13 ).…”

Establishment of a 3-Dimensional Intestinal Cell Model to Simulate the Intestinal Mucosal Immune System for Food Allergy Investigations

“…A previous study has demonstrated the involvement of the Hippo pathway in food allergy using a mouse model ( 12 ). To further validate this finding and check the capability of the 3D intestinal cell model in food allergy research, the activation of the Hippo pathway was determined in this model.…”

“…The total protein from cells was extracted by Tissue Total Protein Lysis Buffer (Sangon Biotech, China), and the Western blot analysis was conducted with indicated antibodies as previously reported ( 12 ). In brief, 40 μg of total protein extract was denatured in loading buffer containing β-mercaptoethanol and SDS at 95°C and then loaded to each lane of a polyacrylamide gel (5% stacking gel and 12% separating gel).…”

“…On the other hand, by using the dendritic cells derived from mouse bone marrow, human peripheral blood mononuclear cells, and THP1 cell line, Tsai and colleagues demonstrated how dust mite allergen Der p 7 activates DCs and T cells ( 11 ). By using a mouse gut epithelial cell line CMT93, Wang and colleagues elucidated the molecular mechanisms of how shrimp allergen tropomyosin irritates the allergenic potential of IEC ( 12 ). Moreover, several studies tried to combine different types of cells to establish a more complex cell model.…”

“…Previous studies have demonstrated the connection between the Hippo pathway and allergy ( 15 ), and the regulation of T cells by the Hippo pathway was also revealed ( 18 , 19 ). Furthermore, Wang and colleagues found that the Hippo pathway involves in the allergenicity of shrimp allergen tropomyosin, provided potential targets for controlling food allergies ( 12 ).…”