scholarly journals Atoh8 is a regulator of intestinal microfold cell (M cell) differentiation

2021 ◽  
Author(s):  
Joel Johnson George ◽  
Laura Martin Diaz ◽  
Markus Ojanen ◽  
Keijo Viiri
Keyword(s):  
Cell Differentiation ◽  
Mucosal Immunity ◽  
M Cells ◽  
M Cell ◽  
Polycomb Repressive Complex 2 ◽  
Salmonella Infections ◽  
Epigenetic Regulator ◽  
Development And Differentiation ◽  
Host Mouse ◽  
Microfold Cells

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, its development and differentiation remains yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. Increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mouse with increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that the population density of intestinal M-cell in the Peyer's patch is regulated by the PRC2 regulated Atoh8.

scholarly journals PRC2 Regulated Atoh8 Is a Regulator of Intestinal Microfold Cell (M Cell) Differentiation

2021 ◽  
Vol 22 (17) ◽  
pp. 9355
Author(s):  
Joel Johnson George ◽  
Laura Martin-Diaz ◽  
Markus J. T. Ojanen ◽  
Rosa Gasa ◽  
Marko Pesu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Mucosal Immunity ◽  
M Cells ◽  
M Cell ◽  
Polycomb Repressive Complex 2 ◽  
Salmonella Infections ◽  
Epigenetic Regulator ◽  
Development And Differentiation ◽  
Microfold Cells

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens, and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, their development and differentiation remain yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development, and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; the absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell-associated markers such as Spi-B and Sox8. In vitro organoid analysis of RankL treated organoid showed an increase of mature marker GP2 expression and other M cell-associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. An increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mice with an increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that PRC2 regulated Atoh8 is one of the factors that regulate the population density of intestinal M cell in the Peyer’s patch.

scholarly journals Polycomb Repressive Complex 2-controlled Essrg regulates intestinal Microfold cell differentiation

2020 ◽  
Author(s):  
Joel Johnson George ◽  
Mikko Oittinen ◽  
Laura Martin-Diaz ◽  
Veronika Zapilko ◽  
Sharif Iqbal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Cell Development ◽  
Polycomb Repressive Complex ◽  
M Cell ◽  
Polycomb Repressive Complex 2 ◽  
Epigenetic Regulator ◽  
Microfold Cells ◽  
Estrogen Related Receptor

AbstractMicrofold cells (M cells) are immunosurveillance epithelial cells located in the Peyer’s patches in the intestine responsible for monitoring and transcytosis of antigens, microorganisms and pathogens. Many transcription factors, e.g., Spi-B and Sox8, necessary to M cell differentiation have been described but the exhaustive set of factors sufficient for differentiation and development of a mature M cell remains elusive. Moreover, the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M cell development has not yet been interrogated. Here, we show that PRC2 regulates a significant set of genes during the M cell differentiation including many transcription factors. Estrogen related receptor gamma (Esrrg) is a novel M cell specific transcription factor acting on a RankL-Rank induced NF-kB pathway, upstream of Sox8 and necessary but not sufficient for a mature M cell marker Gp2 expression. To conclude, with the aid of PRC2 target survey we identified the list of developmental genes specifically implicated in M cell development and Essrg as a necessary factor for Sox8-mediated M cell differentiation.

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

2018 ◽  
Vol 215 (2) ◽  
pp. 501-519 ◽  
Author(s):  
Takashi Kanaya ◽  
Sayuri Sakakibara ◽  
Toshi Jinnohara ◽  
Masami Hachisuka ◽  
Naoko Tachibana ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Tumor Necrosis Factor Receptor ◽  
M Cells ◽  
M Cell ◽  
Antigen Uptake ◽  
Conditional Deletion ◽  
Follicle Associated Epithelium ◽  
Necrosis Factor

M cells are located in the follicle-associated epithelium (FAE) that covers Peyer’s patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell–associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor–associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.

scholarly journals Aging-Related Impairments to M Cells in Peyer’s Patches Coincide With Disturbances to Paneth Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
David S. Donaldson ◽  
Barbara B. Shih ◽  
Neil A. Mabbott
Keyword(s):  
Cell Differentiation ◽  
Paneth Cell ◽  
The Elderly ◽  
Paneth Cells ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
M Cells ◽  
Aging Effects ◽  
M Cell ◽  
Aged Mice

The decline in mucosal immunity during aging increases susceptibility, morbidity and mortality to infections acquired via the gastrointestinal and respiratory tracts in the elderly. We previously showed that this immunosenescence includes a reduction in the functional maturation of M cells in the follicle-associated epithelia (FAE) covering the Peyer’s patches, diminishing the ability to sample of antigens and pathogens from the gut lumen. Here, co-expression analysis of mRNA-seq data sets revealed a general down-regulation of most FAE- and M cell-related genes in Peyer’s patches from aged mice, including key transcription factors known to be essential for M cell differentiation. Conversely, expression of ACE2, the cellular receptor for SARS-Cov-2 virus, was increased in the aged FAE. This raises the possibility that the susceptibility of aged Peyer’s patches to infection with the SARS-Cov-2 virus is increased. Expression of key Paneth cell-related genes was also reduced in the ileum of aged mice, consistent with the adverse effects of aging on their function. However, the increased expression of these genes in the villous epithelium of aged mice suggested a disturbed distribution of Paneth cells in the aged intestine. Aging effects on Paneth cells negatively impact on the regenerative ability of the gut epithelium and could indirectly impede M cell differentiation. Thus, restoring Paneth cell function may represent a novel means to improve M cell differentiation in the aging intestine and increase mucosal vaccination efficacy in the elderly.

scholarly journals Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Haaris S Khan ◽  
Vidhya R Nair ◽  
Cody R Ruhl ◽  
Samuel Alvarez-Arguedas ◽  
Jorge L Galvan Rendiz ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Scavenger Receptor ◽  
Cell Receptor ◽  
The Body ◽  
M Cells ◽  
M Cell ◽  
Type Vii Secretion ◽  
Multiple Routes ◽  
Mechanistic Basis ◽  
Microfold Cells

Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.

scholarly journals Maf is a regulator of differentiation for gut immune epithelial cell Microfold cell (M cell)

2021 ◽  
Author(s):  
Joel Johnson George ◽  
Fabio Tadeu Arrojo Martins ◽  
Laura Martin-Diaz ◽  
Keijo Viiri
Keyword(s):  
Transcription Factors ◽  
Critical Role ◽  
Single Layer ◽  
Cell Development ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
M Cells ◽  
M Cell ◽  
Development And Differentiation ◽  
Antigen Presenting

Microfold cells (M cells) are a specialized subset of epithelial intestinal cells responsible for immunosurveillance of the gastrointestinal tract. M cells are located in the Peyer's patches and are crucial for monitoring and the transcytosis of antigens, microorganisms, and pathogens via their mature receptor GP2. A mature M cell with Gp2 receptor aids in the uptake of antigens, which are passed through the single layer of epithelium and presented to underlying antigen-presenting cells and processed further down-stream with B cells, T cells, and dendritic cells. Recent studies revealed several transcription factors and ligands responsible for the development and differentiation of mature M cells however, an exhaustive list of factors remains to be elucidated. Our recent work on the epigenetic regulation of M cell development found 12 critical transcription factors that were controlled by the polycomb recessive complex 2. Musculoaponeurotic fibrosarcoma transcription factor (Maf) was identified as a gene regulated by the polycomb repressive complex (PRC2) during the development of M cells. In this paper, we explore Maf's critical role in M cell differentiation and maturation. Maf falls under the purview of RANKL signaling, is localized in the Peyer's patches of the intestine, and is expressed by M cells. Given that, complete knockout of the Maf gene leads to a lethal phenotype, organoids isolated from Maf knockout mice and treated with RANKL exhibited impaired M cell development and a significant decrease in Gp2 expression. These findings reveal that Maf is an important regulator for M cell development and differentiation.

scholarly journals Characterization of M Cells in Tear Duct-Associated Lymphoid Tissue of Mice: A Potential Role in Immunosurveillance on the Ocular Surface

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuki Oya ◽  
Shunsuke Kimura ◽  
Yutaka Nakamura ◽  
Narumi Ishihara ◽  
Shunsuke Takano ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymphoid Tissue ◽  
Immune Surveillance ◽  
Small Population ◽  
M Cells ◽  
Eye Drops ◽  
M Cell ◽  
Antigen Uptake ◽  
Mucosal Tissues ◽  
Eye Region

The ocular mucosal tissues are exposed to potentially harmful foreign antigens in the air and tear fluid. The tear duct-associated lymphoid tissue (TALT) may contribute to immune surveillance in the eye region. Follicle-associated epithelium (FAE) of TALTs is classified as stratified squamous epithelium and consists of squamous epithelial cells arranged in layers on the basement membrane. In contrast, most mucosa-associated lymphoid tissue is covered by a monolayer of epithelium containing microfold (M) cells. Therefore, antigen uptake and the presence of M cells in TALT are not fully understood. The present study found that a small population of FAE cells in the TALT expressed intestinal M-cell markers, namely Sox8, Tnfaip2, GP2, and OPG. This cell population was identified as functional M cells because of their uptake capacity of luminal nanoparticles. In addition, RANKL, which is essential for M-cell differentiation, was expressed by stroma-like cells at the subepithelial region and its receptor RANK by the FAE in the TALT. The administration of RANKL markedly increased the number of Sox8+ M cells. In contrast, deficiency in OPG, an endogenous inhibitor of RANKL, increased the number of M cells in the TALT. These data demonstrate that the RANKL-RANK axis is essential for M-cell differentiation in the TALT. Furthermore, immunization via eye drops elicited the production of antigen-specific antibodies in tears, which was enhanced by RANKL administration. Thus, TALT M cells play an important role in the immunosurveillance of the eye region.

scholarly journals Role of M Cells in Human Mucosal Immunity to Mycobacterium tuberculosis

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S48-S48
Author(s):  
Vidhya Nair ◽  
Haaris Khan ◽  
Ron Mitchell ◽  
Michael U Shiloh
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virulence Factor ◽  
Mucosal Immunity ◽  
Cell Biology ◽  
Infection Model ◽  
M Cells ◽  
Dependent Manner ◽  
M Cell ◽  
Wide Range

Abstract Background Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a bacterial pathogen that infects roughly one-third of the worldÕs population and causes 1–2 million deaths per year. The current paradigm is that phagocytosis of Mtb by patrolling alveolar macrophages initiates Mtb infection. While this model can account for pulmonary TB, it does not adequately explain the occurrence of extrapulmonary forms of TB that manifest in the absence of obvious lung involvement, such as tuberculous cervical lymphadenitis, also known as scrofula. We hypothesized that specialized epithelial cells called microfold cells (M cells) may be an alternate portal of entry for Mtb. Previously we demonstrated that Mtb is able to transcytose across an epithelial barrier in an M cell dependent manner and that M cell mediated transcytosis is vital for Mtb pathogenesis in a mouse model of tuberculosis. Methods We used an in vitro M-cell mediated translocation assay and a Mtb mutant lacking a key virulence factor, ESAT6. We used biochemistry and genetics to identify a novel receptor for ESAT6. We also developed a novel explanted human adenoid Mtb infection model to study mucosal immunity. Results We now demonstrate that the Mtb virulence factor ESAT6 is necessary and sufficient to mediate binding and transcytosis by M cells in vitro and in vivo, and that uptake of Mtb by M cells requires a unique cell surface ESAT6 receptor. We developed a novel explanted human adenoid model of M cell biology and demonstrate rapid Mtb transcytosis by primary human tissue within 60–120 minutes. Using flow cytometry we find that Mtb is first ingested by M cells and then after transcytosis, by tissue resident antigen-presenting cells. Explanted adenoids from 10 independent donors display a wide range of Mtb uptake. Conclusion We conclude that Mtb ESAT6 is necessary for Mtb uptake by M-cells and that binding and transcytosis require a host receptor. Because explanted adenoids display a wide range of Mtb uptake, M cell mediated transcytosis may confer differential susceptibility to scrofula and disseminated disease. These findings are significant as M cells could potentially serve as the basis for novel therapeutic targets against primary Mtb infection. Disclosures All authors: No reported disclosures.

scholarly journals TNF-α augments RANKL-dependent intestinal M cell differentiation in enteroid cultures

2016 ◽  
Vol 311 (3) ◽  
pp. C498-C507 ◽  
Author(s):  
Megan B. Wood ◽  
Daniel Rios ◽  
Ifor R. Williams
Keyword(s):  
Cell Differentiation ◽  
Protein Kinase ◽  
Three Dimensional ◽  
Mitogen Activated Protein Kinase ◽  
M Cells ◽  
Epithelial Stem Cells ◽  
M Cell ◽  
Gene Encoding ◽  
Tnf Α ◽  
Follicle Associated Epithelium

Microfold (M) cells are phagocytic intestinal epithelial cells in the follicle-associated epithelium of Peyer's patches that transport particulate antigens from the gut lumen into the subepithelial dome. Differentiation of M cells from epithelial stem cells in intestinal crypts requires the cytokine receptor activator of NF-κB ligand (RANKL) and the transcription factor Spi-B. We used three-dimensional enteroid cultures established with small intestinal crypts from mice as a model system to investigate signaling pathways involved in M cell differentiation and the influence of other cytokines on RANKL-induced M cell differentiation. Addition of RANKL to enteroids induced expression of multiple M cell-associated genes, including Spib, Ccl9 [chemokine (C-C motif) ligand 9], Tnfaip2 (TNF-α-induced protein 2), Anxa5 (annexin A5), and Marcksl1 (myristoylated alanine-rich protein kinase C substrate) in 1 day. The mature M cell marker glycoprotein 2 ( Gp2) was strongly induced by 3 days and expressed by 11% of cells in enteroids. The noncanonical NF-κB pathway was required for RANKL-induced M cell differentiation in enteroids, as addition of RANKL to enteroids from mice with a null mutation in the mitogen-activated protein kinase kinase kinase 14 ( Map3k14) gene encoding NF-κB-inducing kinase failed to induce M cell-associated genes. While the cytokine TNF-α alone had little, if any, effect on expression of M cell-associated genes, addition of TNF-α to RANKL consistently resulted in three- to sixfold higher levels of multiple M cell-associated genes than RANKL alone. One contributing mechanism is the rapid induction by TNF-α of Relb and Nfkb2 (NF-κB subunit 2), genes encoding the two subunits of the noncanonical NF-κB heterodimer. We conclude that endogenous activators of canonical NF-κB signaling present in the gut-associated lymphoid tissue microenvironment, including TNF-α, can play a supportive role in the RANKL-dependent differentiation of M cells in the follicle-associated epithelium.

scholarly journals Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis

2019 ◽  
Author(s):  
Haaris S. Khan ◽  
Vidhya R. Nair ◽  
Cody R. Ruhl ◽  
Samuel Alvarez-Arguedas ◽  
Jorge L. Galvan Resendiz ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Scavenger Receptor ◽  
Cell Receptor ◽  
The Body ◽  
M Cells ◽  
M Cell ◽  
Type Vii Secretion ◽  
Multiple Routes ◽  
Mechanistic Basis ◽  
Microfold Cells

AbstractMycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.

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