TTC4 Overexpression Attenuates Allergic Rhinitis via Inhibiting AMPK-Mediated Autophagy.

Abstract

Introduction: IL-33 was regarded as an inducer of Th2 differentiation and autophagy. Imbalanced Th1/Th2 percentage and autophagy play a crucial role in the development of allergic rhinitis (AR). Here, we investigated the role and action mechanism of tetratricopeptide repeat domain 4 (TTC4) in AR development through regulation IL-33 production.

Methods: Cell co-culture was used to explore the effects of IL-33 from nasal mucosal epithelial cells on CD4+T differentiation. Flow cytometry was used to detect Th1 and Th2 cell percentages, and immunofluorescence was performed for autophagosome. Production of IgE, IL-33, and cytokines was detected by ELISA assay. HE staining was carried out for detection of inflammatory damage of the nasal mucosal epithelial tissues in AR model mice.

Results: First, our data proved that TTC4 was lowly expressed in the nasal mucosal epithelial tissues of AR patients and in the IL-13-induced nasal mucosal epithelial cells. Then, we found that TTC4 overexpression obviously reduced IL-13-induced pro-inflammatory cytokines (TNF-α and IL-1β), IgE, and IL-33 production. After co-culture of CD4+T cells and nasal mucosal epithelial cells, overexpression of TTC4 in nasal mucosal epithelial cells promoted Th1-related cytokines production and Th1 differentiation and inhibited Th2-related cytokines production and Th2 differentiation, which was rescued by rIL-33 treatment. In addition, TTC4 increasing inhibited autophagosome formation and LC3II/I and Beclin 1 expression, but promoted p62 expression, which were rescued by rIL-33 treatment. The promotion of TTC4 to AMPK activation and the inhibition of it to mTOR activation were also rescued by rIL-33 treatment. Activation of autophagy could reverse the regulation of TTC4 to CD4+T cells differentiation into Th1 and Th2 phenotypes. At last, our data showed that TTC4 overexpression effectively attenuated allergic symptoms in AR model mice and inflammatory injury in nasal mucosal tissues, reduced Th2-related cytokines, IgE, and IL-33 production, and inhibited AMPK/mTOR signaling-mediated autophagy, which were rescued by autophagy activator.

Conclusion: TTC4 overexpression attenuated allergic symptoms and inflammation via rebalancing Th1/Th2 percentage and inhibiting autophagy of nasal mucosal epithelial cells through inhibition of the production of IL-33. Our experiments may provide novel idea for the treatment of AR.