Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis

Eissa, Nour; Elgazzar, Omar; Hussein, Hayam; Hendy, Geoffrey N.; Bernstein, Çharles N.; Ghia, Jean–Eric

doi:10.3390/biomedicines9020134

Cited by 3 publications

(6 citation statements)

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“…Moreover, isolated peritoneal macrophages produced decreased levels of the anti-inflammatory cytokine IL-10 following PST treatment. However, these effects of PST were only seen in mice with DSS-induced colitis, and no effects were seen in control mice [115], suggesting that PST alone is insufficient to drive macrophage inflammation.…”

Section: Pst Promotes Inflammatory Responses By Macrophagesmentioning

confidence: 92%

“…Although the immune system's involvement was not shown in this experiment, the permeability of the gut barrier is well known to be regulated by proinflammatory cytokines, such as TNF-α and Interferon γ (IFN-γ), that increase the leakiness by altering the levels of tight junction proteins [114]. Indeed, treatment of the Caco-2 epithelial cell line with PST triggered a decrease in the mRNA and protein levels of tight junction components, including Claudin, tight junction protein ZO-1, E-cadherin-1, and Occludin [115].…”

Section: Inflammatory Properties Of Pstmentioning

confidence: 99%

“…Moreover, PST concentrations that are used in experimental settings are often higher than the 20-80 pg/mL or 4-20 pM PST found in the plasma of healthy humans [32,123,124]. Therefore, the reported effects of PST, such as on cytokine production in mice [115], might not be statistically significant nor functionally relevant in humans. Moreover, mouse-and human PST only have around 55.6 % sequence identity [8,105].…”

Section: Synopsis and Future Directionsmentioning

confidence: 99%

“…4). This seems possible because co-incubation of the human intestinal epithelial cell line Caco-2 with PST results in the alteration of tight junction expression [115] and hence can be expected to alter the permeability of epithelial monolayers. As a second example, the increased macrophage activation in diet-induced obese mice treated with PST [137,138] might be a secondary effect of its metabolic roles, for instance, due to the production of chemoattractants by adipocytes [139].…”

Section: Synopsis and Future Directionsmentioning

confidence: 99%

“…As a second example, the increased macrophage activation in diet-induced obese mice treated with PST [137,138] might be a secondary effect of its metabolic roles, for instance, due to the production of chemoattractants by adipocytes [139]. Indeed, evidence suggests that PST modulates adipocytes and epithelial cells directly [45,115]. Pre-treatment of rat adipocytes with PST provokes a dose-dependent decrease in insulin activation measured as the reduction of 2-deoxyglucose uptake [115].…”

Section: Synopsis and Future Directionsmentioning

confidence: 99%

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The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

Ioannidis¹,

Mahata²,

Bogaart³

2022

Peptides

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Section: Pst Promotes Inflammatory Responses By Macrophagesmentioning

confidence: 92%

Section: Inflammatory Properties Of Pstmentioning

confidence: 99%

Section: Synopsis and Future Directionsmentioning

confidence: 99%

Section: Synopsis and Future Directionsmentioning

confidence: 99%

Section: Synopsis and Future Directionsmentioning

confidence: 99%

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The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

Ioannidis¹,

Mahata²,

Bogaart³

2022

Peptides

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Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Muntjewerff

Tang

Lutter

et al. 2020

Preprint

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Background and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

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Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

et al. 2021

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Aim A “leaky” gut barrier has been implicated in the initiation and progression of a multitude of diseases, for example, inflammatory bowel disease (IBD), irritable bowel syndrome and celiac disease. Here we show how pro‐hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352‐372), the most abundant CgA‐derived proteolytic peptide, affect the gut barrier. Methods Colon tissues from region‐specific CST‐knockout (CST‐KO) mice, CgA‐knockout (CgA‐KO) and WT mice were analysed by immunohistochemistry, western blot, ultrastructural and flowcytometry studies. FITC‐dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250‐301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. Results Plasma levels of CST were elevated in IBD patients. CST‐KO mice displayed (a) elongated tight, adherens junctions and desmosomes similar to IBD patients, (b) elevated expression of Claudin 2, and (c) gut inflammation. Plasma FITC‐dextran measurements showed increased intestinal paracellular permeability in the CST‐KO mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST‐KO mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA‐KO mice supplementation with CST and/or PST in CgA‐KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. Conclusion The pro‐hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts by antagonizing PST.

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Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis

Cited by 3 publications

References 56 publications

The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

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