Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling

Kanaya, Takashi; Sakakibara, Sayuri; Jinnohara, Toshi; Hachisuka, Masami; Tachibana, Naoko; Hidano, Shinya; Kobayashi, Takashi; Kimura, Shunsuke; Iwanaga, Toshihiko; Nakagawa, Tomoo; Katsuno, Tatsuro; Kato, Naoya; Akiyama, Taishin; Sato, Toshiro; Williams, Ifor R.; Ohno, Hiroshi

doi:10.1084/jem.20160659

Cited by 74 publications

(88 citation statements)

References 48 publications

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“…RelB is retained in the cytoplasm in its latent inactive form; upon activation, it is rapidly transported into the nucleus. This event is indispensable for the initiation of M-cell differentiation and maturation 11,14 . Immunoblot analysis revealed that, after RANKL administration, the amounts of nuclear RelB in both ileal and cecal epithelium were higher for Opg −/− mice than for WT mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

et al. 2020

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Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPGdependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.

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Section: Resultsmentioning

confidence: 99%

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

et al. 2020

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“…Enteroid cultures have been shown to have useful practical application in the study of the signalling pathways which modulate the differentiation and maintenance of distinct epithelial cell lineages in the murine intestine including Lgr5 + intestinal stem cells [ 6 , 61 ], tuft cells [ 20 ] and antigen-sampling M cells [ 3 , 19 , 21 , 22 ]. The 3D nature of the enteroids with a layer of epithelial cells surrounding a central, closed, lumen has also been shown to be an effective system in which to model mucosal permeability [ 62 ] and the interactions of mucosally-acquired pathogenic bacteria [ 24 ], viruses [ 25 ] and protozoa [ 26 ] with the gut epithelium.…”

Section: Discussionmentioning

confidence: 99%

Development of in vitro enteroids derived from bovine small intestinal crypts

Hamilton

Young

Jayaraman

et al. 2018

Vet Res

116

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Cattle are an economically important domestic animal species. In vitro 2D cultures of intestinal epithelial cells or epithelial cell lines have been widely used to study cell function and host–pathogen interactions in the bovine intestine. However, these cultures lack the cellular diversity encountered in the intestinal epithelium, and the physiological relevance of monocultures of transformed cell lines is uncertain. Little is also known of the factors that influence cell differentiation and homeostasis in the bovine intestinal epithelium, and few cell-specific markers that can distinguish the different intestinal epithelial cell lineages have been reported. Here we describe a simple and reliable procedure to establish in vitro 3D enteroid, or “mini gut”, cultures from bovine small intestinal (ileal) crypts. These enteroids contained a continuous central lumen lined with a single layer of polarized enterocytes, bound by tight junctions with abundant microvilli on their apical surfaces. Histological and transcriptional analyses suggested that the enteroids comprised a mixed population of intestinal epithelial cell lineages including intestinal stem cells, enterocytes, Paneth cells, goblet cells and enteroendocrine cells. We show that bovine enteroids can be successfully maintained long-term through multiple serial passages without observable changes to their growth characteristics, morphology or transcriptome. Furthermore, the bovine enteroids can be cryopreserved and viable cultures recovered from frozen stocks. Our data suggest that these 3D bovine enteroid cultures represent a novel, physiologically-relevant and tractable in vitro system in which epithelial cell differentiation and function, and host–pathogen interactions in the bovine small intestine can be studied.Electronic supplementary materialThe online version of this article (10.1186/s13567-018-0547-5) contains supplementary material, which is available to authorized users.

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“…TRAF6 knockout mice are prenatal and postnatal lethal [30]. Conditional knockout models revealed essential roles for TRAF6 in a variety of immune cellular backgrounds but also in epithelial cell types [31][32][33][34], indicating how important this factor is for normal cellular homeostasis. More recently, TRAF6 was also implicated in cancer signalling, by regulating epithelial to mesenchymal transition (EMT) in colon cancer [35], DNA damage in breast cancer backgrounds [36], and involvement in autophagy responses [37].…”

Section: Discussionmentioning

confidence: 99%

HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

D'Ignazio

Shakir

Batie

et al. 2020

IJMS

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NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is understood regarding how HIF-1β contributes to NF-κB signalling. Here, we demonstrate that HIF-1β is required for full NF-κB activation in cells following canonical and non-canonical stimuli. We found that HIF-1β specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1β binds to the TRAF6 gene and controls its expression independently of HIF-1α. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1β. These results indicate that HIF-1β is an important regulator of NF-κB with consequences for homeostasis and human disease.

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Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling

Abstract: TRAF6 is essential for RANK-mediated NF-κB activation and is involved in the development of several types of cells. Kanaya et al. demonstrate that RANK–TRAF6-mediated NF-κB is essential for the development of M cells and FAE.

Cited by 74 publications

References 48 publications

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

Development of in vitro enteroids derived from bovine small intestinal crypts

HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

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