mTOR sustains inflammatory response in celiac disease

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals.
• The precise mechanisms amplifying mucosal inflammation in CD remain incompletely understood.
• The mammalian target of Rapamycin (mTOR) pathway regulates immune cell metabolism and function.

Purpose of the Study:

• To investigate the role of the mTOR pathway in sustaining immune responses in active CD.
• To determine if mTOR activation occurs in the intestinal epithelium during active CD.
• To explore the impact of gluten peptides and inflammatory cytokines on mTOR signaling in CD.

Main Methods:

• Analysis of duodenal biopsy samples from active CD patients and controls.
• Assessment of phosphorylated mTOR and its downstream targets (p-4EBP, p-Rictor) via Western blotting.
• Stimulation of mucosal explants with digested gliadin and cytokines (IFN-γ, IL-21), followed by cytokine blockade.
• Treatment of explants with rapamycin (mTORC1 inhibitor) and measurement of IL-15 production.

Main Results:

• Increased expression of active (phosphorylated) mTOR was observed in duodenal biopsies from active CD patients.
• mTOR activation was primarily localized to the epithelial compartment in active CD, associated with elevated p-4EBP.
• Stimulation with digested gliadin or cytokines (IFN-γ/IL-21) increased p-4EBP in inactive CD explants.
• Rapamycin treatment reduced p-4EBP and IL-15 production in active CD mucosal explants.

Conclusions:

• Active CD is characterized by mTORC1 activation within the duodenal epithelial compartment.
• This epithelial mTORC1 activation may contribute to sustained mucosal inflammation and IL-15 production in celiac disease.
• Targeting mTORC1 could represent a potential therapeutic strategy for active celiac disease.