Epithelial–stromal interaction via <scp>N</scp>otch signaling is essential for the full maturation of gut‐associated lymphoid tissues

Obata, Yuichi; Kimura, Shunsuke; Nakato, Gaku; Iizuka, Keito; Miyagawa, Yurika; Nakamura, Yutaka; Furusawa, Yukihiro; Sugiyama, Machiko; Suzuki, Keiichiro; Ebisawa, Masashi; Fujimura, Y; Yoshida, Hisahiro; Iwanaga, Toshihiko; Hase, Koji; Ohno, Hiroshi

doi:10.15252/embr.201438942

Cited by 12 publications

(12 citation statements)

References 24 publications

(35 reference statements)

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“…In addition, for the route of L. bulgaricus 2038 and S. thermophilus 1131 to be recognized by DCs, it is deduced that they are transcytosed to the small intestinal LP via M cells, present on the follicle-associated epithelium (FAE), which have the role to transport luminal organisms passing through the LP [26]. It has been reported that the mucin layer is thinner in the FAE than villous because goblet cell differentiation is diminished by Notch signal from stromal cells underneath the FAE [27,28]. Therefore, it is estimated that administered L. bulgaricus 2038 and S. thermophilus 1131 readily access M cells and are transported.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

2019

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Accumulating evidence clarifies that intestinal barrier function, for example, by the mucus layer, antimicrobial peptides, immune systems, and epithelial tight junctions, plays crucial roles in maintaining our health. We reported previously that yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 induced the gene expression of the regenerating family member 3 (REG3) family, which encodes antimicrobial peptides in the small intestine, although it was unclear how the yogurt activated the intestinal cells related to it. Here, we evaluated the cytokine production from the intestinal immune cells stimulated by these strains in vitro and in vivo to elucidate the mechanism for the induction of the REG3 family by the yogurt. The results showed that stimulation by both strains induced interleukin (IL)-23 production from bone marrow-derived dendritic cells (DCs) and IL-22 production from small intestinal lamina propria (LP) cells. In addition, oral administration of these strains to mice increased IL-23p19+ LPDCs and IL-22+ type 3 innate lymphoid cells and induced the expression of Reg3g in small intestinal tissue. Moreover, we showed that the activities for the induction of IL-23 by DCs were strain dependent on L. bulgaricus and S. thermophilus and that S. thermophilus 1131, which is the predominant species in the yogurt, exhibited relatively higher activity compared to the other strains of S. thermophilus. Our findings suggested that these yogurt starter strains, L. bulgaricus 2038 and S. thermophilus 1131, have the potential to maintain and improve intestinal barrier function by stimulating immune cells in the LP.

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Section: Discussionmentioning

confidence: 99%

Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

2019

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“…The FAE in PP is formed at the late stage of fetal development as described above. We previously reported that LTo cell-mediated activation of epithelial Notch signaling contributes to the organization and integrity of the FAE [ 21 ]. Activation of epithelial Notch signaling suppresses goblet cell differentiation as described below and secures CCL20 expression in the FAE, facilitating full maturation of PPs and isolated lymphoid follicles.…”

Section: Formation Of Peyer’s Patches and The Faementioning

confidence: 99%

“…Such self-regulation of epithelial cell populations in the intestine is termed lateral inhibition. In PPs, stromal cells beneath the FAE constitutively express a Notch ligand, Dll1 [ 21 , 33 ], indicating that secretory cell lineages in the FAE are suppressed by stromal Notch ligands (Fig. 1 ).…”

Section: Characterization Of the Faementioning

confidence: 99%

“…1 ). The inactivation of the Notch signal by genetic ablation of RBP-J in intestinal epithelial cells (RBP-J ΔIEC ) markedly increases the number of goblet cells in both the FAE and villous epithelium [ 21 ]. As a consequence, RBP-J ΔIEC mice are defective in maturation of PPs and isolated lymphoid follicles at least partly because of downregulated expression of CCL20, which is mainly produced by enterocytes, but not goblet cells, during the developmental stage.…”

Section: Characterization Of the Faementioning

confidence: 99%

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M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance

2018

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The follicle-associated epithelium (FAE) covering mucosa-associated lymphoid tissue is distinct from the villous epithelium in cellular composition and functions. Interleukin-22 binding protein (IL-22BP), provided by dendritic cells at the sub-epithelial dome region, inhibits the IL-22-mediated secretion of antimicrobial peptides by the FAE. The Notch signal from stromal cells underneath the FAE diminishes goblet cell differentiation. These events dampen the mucosal barrier functions to allow luminal microorganisms to readily gain access to the luminal surface of the FAE. Furthermore, receptor activator of nucleic factor-kappa B ligand (RANKL) from a certain stromal cell type induces differentiation into microfold (M) cells that specialize in antigen uptake in the mucosa. Microfold (M) cells play a key role in mucosal immune surveillance by actively transporting external antigens from the gut lumen to the lymphoid follicle. The molecular basis of antigen uptake by M cells has been gradually identified in the last decade. For example, GPI-anchored molecules (e.g., glycoprotein 2 (GP2) and cellular prion protein (PrPC)) and β1-integrin facilitate the transport of specific types of xenobiotics. The antigen transport by M cells initiates antigen-specific mucosal immune responses represented by the induction of secretory immunoglobulin A (S-IgA). Meanwhile, several invasive pathogens exploit M cells as a portal to establish a systemic infection. Recent findings have uncovered the molecular machinery of differentiation and functions of M cells.

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“…The contribution of lymphotoxin-β signaling to peripheral lymphoid tissue development is well established (10, 11). CCL20 and CXCL16, both expressed in the intestinal epithelium, have also been implicated in GALT formation in mice (31-34). By restraining NF-κB activation, p38α signaling might regulate the expression of these GALT-related NF-κB target genes in IECs.…”

Section: Resultsmentioning

confidence: 99%

Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling

Caballero-Franco

Gumá

Choo

et al. 2016

The Journal of Immunology

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The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. Here we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a non-cell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy.

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Epithelial–stromal interaction via Notch signaling is essential for the full maturation of gut‐associated lymphoid tissues

Cited by 12 publications

References 24 publications

Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance

Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling

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