Deletion of Endogenous Neuregulin-4 Limits Adaptive Immunity During Interleukin-10 Receptor-Neutralizing Colitis

Area of Science:

• Gastroenterology
• Immunology
• Molecular Biology

Background:

• Growth factors like neuregulin-4 (NRG4) are vital for intestinal health.
• Exogenous NRG4 aids colonocyte survival and reduces acute inflammation.
• The role of endogenous NRG4 in colitis remains unclear.

Purpose of the Study:

• To investigate the function of endogenous NRG4 in adaptive and innate immune response models of colitis.
• To elucidate the molecular mechanisms by which NRG4 influences intestinal inflammation.

Main Methods:

• Utilized NRG4 knockout (NRG4-/-) and wild-type mice in IL-10R neutralization (adaptive) and DSS (innate) colitis models.
• Assessed disease severity via histology, cytokine levels, lipocalin-2, and immune cell profiling.
• Analyzed gene expression changes using RNA sequencing and qPCR.

Main Results:

• NRG4-/- mice showed reduced inflammation and CD8+ T cells in adaptive colitis but increased damage and impaired recovery in innate colitis.
• Loss of NRG4 led to decreased ST3GAL4 (sialyltransferase) expression in colons.
• NRG4 directly regulates ST3GAL4 expression in colon epithelial cells.

Conclusions:

• Endogenous NRG4 regulates colonic ST3GAL4, influencing CD8+ T cell recruitment in adaptive colitis.
• NRG4 deficiency worsens injury in innate immune-driven colitis models.
• NRG4 has distinct, context-dependent roles in intestinal inflammation.