1. Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa
- Author
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Stamatia Papoutsopoulou, Joseph Tang, Ahmed H. Elramli, Jonathan M. Williams, Nitika Gupta, Felix I. Ikuomola, Raheleh Sheibani-Tezerji, Mohammad T. Alam, Juan R. Hernández-Fernaud, Jorge H. Caamaño, Chris S. Probert, Werner Muller, Carrie A. Duckworth, and D. Mark Pritchard
- Subjects
Lipopolysaccharides ,Proteomics ,Lydia Becker Institute ,Physiology ,Plasma Cells ,immunoglobulins ,Immunoglobulins ,RelB ,Immunoglobulin A/metabolism ,NF-kappa B p52 Subunit/genetics ,NF-κB ,plasma cells ,Mice ,Nfkb2 ,NF-kappa B p52 Subunit ,ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation ,Physiology (medical) ,Animals ,Intestinal Mucosa ,Immunoglobulins/metabolism ,Hepatology ,Plasma Cells/metabolism ,NF-kappa B ,Gastroenterology ,Lipopolysaccharides/pharmacology ,Immunoglobulin A ,intestinal mucosa ,NF-kappa B/metabolism ,Intestinal Mucosa/metabolism - Abstract
The alternative (noncanonical) nuclear factor-κB (NF-κB) signaling pathway predominantly regulates the function of the p52/RelB heterodimer. GermlineiNfkb/i2 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 adultiNfkb2/isup-/-/supmice. 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 iniNfkb2/isup-/-/supmice. 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 ofiNfkb2/isup-/-/supmice. This phenotype was even more striking in the small intestinal mucosa ofiRelB/isup-/-/supmice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as theiriRelB/isup+/+/supwild-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.bNEWamp; NOTEWORTHY/bNovel transcriptomic analysis of murine proximal intestinal mucosa revealed an unexpected B cell signature iniNfkb2/isup-/-/supmice. In-depth analysis revealed a defect in the CD38+ B cell population and a gut-specific dysregulation of immunoglobulin levels.
- Published
- 2022
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