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

S Papoutsopoulou, J Tang, AH Elramli, JM Williams, N Gupta, FI Ikuomola, R Sheibani-Tezerji, MT Alam, JR Hernández-Fernaud, JH Caamano, CS Probert, Werner Muller, DM Pritchard

Research output: Contribution to journalArticlepeer-review

Abstract

The alternative (noncanonical) nuclear factor-κB (NF-κB) signaling 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. We applied high-throughput RNA-Seq and proteomic analyses to characterize 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. 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, cluster of differentiation (CD)138-positive 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. NF-κB2/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.

Original languageEnglish
Pages (from-to)G306-G317
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume323
Issue number4
Early online date12 Sept 2022
DOIs
Publication statusPublished - 1 Oct 2022

Keywords

  • NF-κB
  • Nfkb2
  • RelB
  • immunoglobulins
  • intestinal mucosa
  • plasma cells
  • Lipopolysaccharides/pharmacology
  • NF-kappa B p52 Subunit/genetics
  • Immunoglobulins/metabolism
  • Immunoglobulin A/metabolism
  • Plasma Cells/metabolism
  • Animals
  • Intestinal Mucosa/metabolism
  • Proteomics
  • Mice
  • NF-kappa B/metabolism

Research Beacons, Institutes and Platforms

  • Lydia Becker Institute

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