Mouse and human Notch-1 regulate mucosal immune responses

Abstract

The Notch-1 signaling pathway is responsible for homeostatic tight junction expression in vitro, and promotes barrier function in vivo in the RAG1-adoptive transfer model of colitis. In this study, we sought to determine the role of colonic Notch-1 in the lymphoepithelial crosstalk in health and disease. We utilized in vivo and in vitro knockdown to target the expression of Notch-1. We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and upon inflammatory stimulus. Notch-1 expression modulates mucosal chemokine and cytokine secretion, and FoxP3 and effector T-cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium through crosstalk with the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathways that, in turn, elicits T-cell responses. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut. Our findings highlight an indispensable role for Notch-1-mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial proinflammatory responses.

Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate

“…There are numerous studies demonstrating that Notch1 regulates the intestinal barrier. (Turgeon et al, 2013, Mathern et al, 2014, Min et al, 2014, Obata et al, 2012, Dahan et al, 2011) siRNA knockdown of Notch1 in vitro (i.e., Caco-2 cells) is associated with impaired intestinal cell monolayer integrity and decreased expression of the tight junction protein occludin. (Dahan et al, 2011) Downregulation of Notch1 in vivo is associated with gut leakiness and alterations in tight junction protein expression and colon inflammation.…”

“…(Dahan et al, 2011) Downregulation of Notch1 in vivo is associated with gut leakiness and alterations in tight junction protein expression and colon inflammation. (Mathern et al, 2014, Dahan et al, 2011, Min et al, 2014) Notch1 cleavage product NICD pairs with the transcription factor Rbpj in mice to activate canonical Notch1 target genes and in vivo knockout of Rbpj in mice causes intestinal hyperpermeability and colitis. (Obata et al, 2012) A recent study in diabetic mice showed that decreased NICD/Hes1 expression resulted in intestinal hyperpermeability.…”

Molecular mechanisms of Notch1-mediated neuronal cell death in ischemic stroke

“…By contrast, there is no effect of γ-secretase inhibition on the expression of both phosphorylated-and total-p38 and ERK under OGD conditions. Although there are a number of studies that show Notch signaling regulates the p38 pathway in different cell types and disease conditions (Song et al 2002;Mathern et al 2014), there is no clear evidence of Notch activation in the regulation of p38 in neurons following ischemic conditions in this study.…”

TGF-β Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota

“…Notch signaling is transferred by the direct contact between a cell expressing Notch ligands and a cell expressing Notch receptors (45). Some studies have reported Notch-associated crosstalk between immune cells and the epithelium (46,47); however, Notch signaling between DCs and the epithelium has not been demonstrated. The expression of Notch ligands was increased in the intestines of human IBD, and activated Notch signaling was associated with downregulated goblet cell differentiation and mucin formation (48).…”