Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses

Area of Science:

• Gastroenterology
• Immunology
• Molecular Biology

Background:

• The precise role of colonic epithelium in ulcerative colitis (UC) pathogenesis is not fully understood.
• T helper-17 (Th17) cells are implicated in UC, but their recruitment mechanisms via epithelial cells require elucidation.

Purpose of the Study:

• To investigate the role of mTOR complex 1 (mTORC1) in colonic epithelial cells during UC.
• To identify the molecular mechanisms linking epithelial mTORC1 activation to Th17 cell recruitment and UC development.

Main Methods:

• Utilized mouse models with disrupted TSC1 (mTORC1 inhibitor) or RPTOR (mTORC1 component) in colonic epithelia.
• Assessed UC severity, Th17 cell infiltration, and expression of key inflammatory mediators (COX-2, IL-1, IL-6, IL-23).
• Investigated the transcriptional regulation of COX-2 by mTORC1 and STAT3 using molecular biology techniques.

Main Results:

• Hyperactivation of mTORC1 in colonic epithelia aggravated UC, while its inhibition ameliorated the disease.
• TSC1 deficiency increased, and RPTOR ablation decreased, expression of COX-2, IL-1, IL-6, IL-23, and Th17 infiltration.
• mTORC1 phosphorylates STAT3, enhancing COX-2 promoter binding and expression; this correlation was observed in human UC tissues.

Conclusions:

• Epithelial mTORC1 signaling is crucial for UC pathogenesis by promoting Th17 cell recruitment.
• The mTORC1-STAT3-COX-2 axis represents a novel mechanism in UC development.
• Targeting epithelial mTORC1 or COX-2 may offer therapeutic strategies for ulcerative colitis.