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

Abstract

BACKGROUND:

Growth factors are essential for maintenance of intestinal health. We previously showed that exogenous neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective against acute models of intestinal inflammation. However, the function(s) of endogenous NRG4 are not well understood. Using NRG4-/- mice, we tested the role of endogenous NRG4 in models of colitis skewed toward either adaptive (interleukin-10 receptor [IL-10R] neutralization) or innate (dextran sulfate sodium [DSS]) immune responses.

METHODS:

NRG4-/- and wild-type cage mate mice were subjected to chronic IL-10R neutralization colitis and acute DSS colitis. Disease was assessed by histological examination, inflammatory cytokine levels, fecal lipocalin-2 levels, and single cell mass cytometry immune cell profiling. Homeostatic gene alterations were evaluated by RNA sequencing analysis from colonic homogenates, with real-time quantitative polymerase chain reaction confirmation in both tissue and isolated epithelium.

RESULTS:

During IL-10R neutralization colitis, NRG4-/- mice had reduced colonic inflammatory cytokine expression, histological damage, and colonic CD8+ T cell numbers vs wild-type cage mates. Conversely, in DSS colitis, NRG4-/- mice had elevated cytokine expression, fecal lipocalin-2 levels, and impaired weight recovery. RNA sequencing showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in NRG4-null colons, which was verified in both tissue and isolated epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment.

CONCLUSIONS:

NRG4 regulates colonic epithelial ST3GAL4 and thus may allow for robust recruitment of CD8+ T cells during adaptive immune responses in colitis. On the other hand, NRG4 loss exacerbates injury driven by innate immune responses.

• Authors: Jessica K Bernard, Edie B Bucar, Cambrian Y Liu, Kay Katada, Mary K Washington, Michael A Schumacher, Mark R Frey
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 29 Issue 11 Pg. 1778-1792 (11 02 2023) ISSN: 1536-4844 [Electronic] England
• PMID: 37265326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• neuregulin-4
• Lipocalin-2
• Cytokines
• Dextran Sulfate

Topics

• Mice
• Animals
• Lipocalin-2 (metabolism)
• Intestinal Mucosa (pathology)
• Colitis (pathology)
• Adaptive Immunity
• Cytokines (metabolism)
• Colon (pathology)
• Dextran Sulfate
• Mice, Inbred C57BL
• Disease Models, Animal
• Mice, Knockout