Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity

Rochman, Mark; Travers, Jared; Abonia, J. Pablo; Caldwell, Julie M.; Rothenberg, Marc E.

doi:10.1172/jci.insight.96789

Cited by 26 publications

(23 citation statements)

References 60 publications

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“…Likewise, upon submitting Synpo −/− mice to DSS colitis, which essentially effaces the intestinal epithelial monolayer by damaging the IECs, a similar pattern to the kidney injury induced by protamine sulfate was revealed as DSS elicited significantly worse disease as a result of SYNPO loss. Correspondingly, SYNPO dysregulation and ensuing barrier and motility dysfunction are apparent in another inflammatory mucosal disease, eosinophilic esophagitis (48). Furthermore, genome-wide association studies of IBD and Crohn's disease show possible significant single nucleotide polymorphisms in the genomic region of SYNPO (49,50), and microarray analysis has demonstrated differential expression of SYNPO2 (also called myopodin), a SYNPO homolog (51), in patients with ulcerative colitis (52).…”

Section: Discussionmentioning

confidence: 99%

Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

Wang

Lee

Campbell³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

188

137

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The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies inSynpo-deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.

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Section: Discussionmentioning

confidence: 99%

Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

Wang

Lee

Campbell³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

188

137

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“…Forced expression of SYNPO in esophageal epithelial cells grown at the ALI resulted at the IBF accompanied by transcriptional changes in structural genes. 57 These collective data indicate that altered esophageal epithelial integrity is a critical contributor to allergic inflammation in patients with EoE.…”

Section: Epithelial Barrier Dysfunction In Patients With Eoementioning

confidence: 93%

“…47,56 In addition, expression of the actinrelated protein synaptopodin (SYNPO), which is involved in regulating the esophageal epithelial barrier, is limited to basal layer cells in the homeostatic esophagus, whereas its expression expands into the suprabasal zone in patients with EoE. 57 Consistent with the role of BMP signaling in squamous epithelial differentiation, the BMP inhibitor FST is expressed in esophageal progenitors, and increased expression of FST in the suprabasal cells is linked to hyperproliferation. 41 Taken together, these findings demonstrate a previously underappreciated complexity of esophageal epithelial responses during homeostasis and EoE.…”

Section: Properties Of the Esophageal Epitheliummentioning

confidence: 99%

“…These genes include CCL26, neurotrophic receptor tyrosine kinase 1 (NTRK1), SYNPO, and CAPN14. 57,[98][99][100] In the case of CAPN14, the EoE risk variant rs76562819 is localized in the peak of histone H3 lysine 27 acetylation, which is dynamically regulated by IL-13 stimulation. Importantly, CAPN14 was expressed in a haplotype-dependent manner, with subjects with the risk allele expressing 30% less CAPN14 than those without the risk haplotype.…”

Section: Genetic and Epigenetic Mechanisms In Epithelial Responses Inmentioning

confidence: 99%

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Epithelial origin of eosinophilic esophagitis

Rochman

Azouz

Rothenberg

2018

Journal of Allergy and Clinical Immunology

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Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

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“…Transcriptomic studies have identified others associated with disease, including SPINK7 and SLC9A3 (4,5). Histologic and ultrastructural studies revealed increased intercellular spaces and reduced desmosomal infrastructure (6)(7)(8), functional studies identified increased impedance (9), and molecular examinations determined key roles for inflammatory molecules including the cytokine IL-13 in diminishing epithelial barrier (2,4,10). These processes are also common to other atopic disorders.…”

Section: Introductionmentioning

confidence: 95%

Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis

Masterson¹,

Biette²,

Hammer³

et al. 2019

Journal of Clinical Investigation

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Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity

Cited by 26 publications

References 60 publications

Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

Epithelial origin of eosinophilic esophagitis

Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis

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