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

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.

Automated summary

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.