ER stress modulates the immune regulatory ability in gut M2 cells of patients with ulcerative colitis

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Macrophages (Mφ) are key immune cells in the colon.
• Ulcerative colitis (UC) involves dysregulated immune responses in the gut.
• M2 macrophages play a role in immune regulation and tissue repair.

Purpose of the Study:

• To characterize the immune regulatory function of Mφ from UC patient colon lavage fluid (CLF).
• To investigate the role of endoplasmic reticulum (ER) stress in UC M2 macrophages.
• To identify molecular mechanisms underlying impaired immune suppression in UC.

Main Methods:

• Isolation and characterization of Mφ from UC patient CLF.
• Analysis of M2 Mφ abundance and immune suppressive function.
• Detection of ER stress markers and gene expression analysis (XBP1, PD-L1, Rnf20).
• Functional assays involving Rnf20 inhibition and experimental colitis models.

Main Results:

• Mφs constituted a significant portion of CLF cells (21.3%).
• UC M2 Mφs exhibited reduced abundance and weaker immune suppressive function.
• High ER stress markers and a negative correlation between spliced X box binding protein-1 (XBP1) and programmed death ligand-1 (PD-L1) were found in UC M2 Mφs.
• XBP1 promoted Rnf20 expression, which decreased PD-L1 and impaired immune suppression.
• Rnf20 inhibition restored M2 Mφ immune capacity and suppressed experimental colitis.

Conclusions:

• ER stress impairs M2 Mφ immune regulatory function in UC.
• The XBP1-Rnf20-PD-L1 axis is a key mechanism in UC-associated immune dysfunction.
• Targeting Rnf20 may represent a therapeutic strategy for restoring immune homeostasis in UC.