Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa

Papoutsopoulou, Stamatia; Tang, Joseph; Elramli, Ahmed H.; Williams, Jonathan M.; Gupta, Nitika; Ikuomola, Felix I.; Sheibani-Tezerji, Raheleh; Alam, Mohammad T.; Hernández-Fernaud, Juan R.; Caamaño, Jorge H.; Probert, Chris S.; Muller, Werner; Duckworth, Carrie A.; Pritchard, D. Mark

Abstract

Background & aims: The alternative (non-canonical) nuclear factor-kB (NF-kB) signalling pathway predominantly regulates the function of the p52/RelB heterodimer. Germline Nfkb2 deficiency in mice leads to loss of p100/p52 protein and offers protection against a variety of gastrointestinal conditions, including azoxymethane/dextran sulfate sodium (DSS)-induced colitis-associated cancer and lipopolysaccharide (LPS)-induced small intestinal epithelial apoptosis. However, the common underlying protective mechanisms have not yet been fully elucidated. Methods: We applied high throughput RNASeq and proteomic analyses to characterise the transcriptional and protein signatures of the small intestinal mucosa of naïve adult Nfkb2-/- mice. Those data were validated by immunohistochemistry and quantitative ELISA using both small intestinal tissue lysates and serum. Results: We identified a B-lymphocyte defect as a major transcriptional signature in the small intestinal mucosa and immunoglobulin A as the most downregulated protein by proteomic analysis in Nfkb2-/- mice. Small intestinal immunoglobulins were dramatically dysregulated, with undetectable levels of immunoglobulin A and greatly increased amounts of immunoglobulin M being detected. The numbers of IgA-producing, CD138+ve plasma cells were also reduced in the lamina propria of the small intestinal villi of Nfkb2-/- mice. This phenotype was even more striking in the small intestinal mucosa of RelB-/- mice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as their RelB+/+ wild-type counterparts. Conclusions: NF-kB2/p52 deficiency confers resistance to LPS-induced small intestinal apoptosis and also appears to regulate the plasma cell population and immunoglobulin levels within the gut.

Citation

Papoutsopoulou, S., Tang, J., Elramli, A. H., Williams, J. M., Gupta, N., Ikuomola, F. I., …Pritchard, D. M. (2022). Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa. American Journal of Physiology - Gastrointestinal and Liver Physiology, 323(4), G306-G317. https://doi.org/10.1152/ajpgi.00037.2022

• Journal Article Type: Article
• Acceptance Date: Jul 22, 2022
• Publication Date: Oct 1, 2022
• Deposit Date: Sep 13, 2022
• Publicly Available Date: Sep 27, 2022
• Journal: American Journal of Physiology-Gastrointestinal and Liver Physiology
• Print ISSN: 0193-1857
• Electronic ISSN: 1522-1547
• Publisher: American Physiological Society
• Peer Reviewed: Peer Reviewed
• Volume: 323
• Issue: 4
• Pages: G306-G317
• DOI: https://doi.org/10.1152/ajpgi.00037.2022
• Keywords: Physiology (medical); Gastroenterology; Hepatology; Physiology
• Additional Information: Received: 2022-02-10; Revised: 2022-07-19; Accepted: 2022-07-19; Published: 2022-09-12