Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 323, Issue 4, Pages G306-G317Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00037.2022
Keywords
intestinal mucosa; immunoglobulins; plasma cells; NF-KB; Nfkb2; RelB
Categories
Funding
- SysmedIBD project
- European Community Seventh Framework Program [305564]
- tenure-track fellowship from the University of Liverpool
- Libyan Embassy PhD studentship funding
- Wellcome Trust [102172/B/13/Z]
- Wellcome Trust [102172/B/13/Z] Funding Source: Wellcome Trust
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NF-KB signaling pathway plays important roles in regulating cell function and immune response. In this study, we identified B cell defect and dysregulation of immunoglobulin levels in the small intestinal mucosa of Nfkb2-/- mice using transcriptomic and proteomic analysis. NF-KB2/p52 deficiency not only increases resistance to LPS-induced cell apoptosis in the small intestine, but also regulates the plasma cell population and immunoglobulin levels within the gut.
The alternative (noncanonical) nuclear factor -KB (NF -KB) signaling pathway predominantly regulates the function of the p52/RelB heter-odimer. 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 eluci-dated. We applied high-throughput RNA-Seq and proteomic analyses to characterize the transcriptional and protein signatures of the small intestinal mucosa of naive 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 in-testinal 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-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.NEW & NOTEWORTHY Novel transcriptomic analysis of murine proximal intestinal mucosa revealed an unexpected B cell signa-ture in Nfkb2-/- mice. In-depth analysis revealed a defect in the CD38 + B cell population and a gut-specific dysregulation of immunoglobulin levels.
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