Dataset Information

Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction.

ABSTRACT: Age-associated decay of intercellular interactions impairs the cells' capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an uncharacterized phosphorylation of a low-abundant actin variant, ACT-5, compromises integrity of the C. elegans intestinal barrier and accelerates pathogenesis. Age-related loss of the heat-shock transcription factor, HSF-1, disrupts the JUN kinase and protein phosphatase I equilibrium which increases ACT-5 phosphorylation within its troponin binding site. Phosphorylated ACT-5 accelerates decay of the intestinal subapical terminal web and impairs its interactions with cell junctions. This compromises barrier integrity, promotes pathogenesis, and drives mortality. Thus, we provide the molecular mechanism by which age-associated loss of specialized actin networks impacts tissue integrity.

SUBMITTER: Egge N

PROVIDER: S-EPMC6897307 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction.

Egge Nathan N Arneaud Sonja L B SLB Wales Pauline P Mihelakis Melina M McClendon Jacob J Fonseca Rene Solano RS Savelle Charles C Gonzalez Ian I Ghorashi Atossa A Yadavalli Sivaramakrishna S Lehman William J WJ Mirzaei Hamid H Douglas Peter M PM

Developmental cell 20191201 5

Age-associated decay of intercellular interactions impairs the cells' capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an uncharacterized phosphorylation of a low-abundant a ...[more]

PMID: 31794717

Similar Datasets

Project description:BACKGROUND: Although clinical and experimental studies have demonstrated a correlation between obstructive jaundice and the development of sepsis, the mechanism has not been fully elucidated. PURPOSE: The aim of this study was to investigate the influence of biliary obstruction on bacterial translocation as a possible source of infection in cases of obstructive jaundice. MATERIAL AND METHODS: Two groups of 12 Wistar rats were examined: rats subjected to common bile duct (CBD) ligation (group A) and rats subjected to a sham operation (group B). After 7 days, blood samples were taken and liver, spleen, and mesenteric lymph nodes (MLNs) from the ileocecal area were removed, divided into small pieces, and cultured. Quantitative culture results were determined by the number of colony-forming units (CFU) per milliliter of homogenate. Bacterial translocation was defined as the presence of a positive culture of MLNs, blood, liver, and/or spleen. Samples for histopathological examination were taken from the mucosa of the ileum and the colon and evaluated for inflammatory and destructive changes. RESULTS: There was no evidence of bacterial translocation to MLNs, blood, spleen, or liver detected in any of the 12 sham-operated control rats. In contrast, bacterial translocation was demonstrated in 8 of the 12 CBD-ligated rats (P < 0.01). In all eight cases in which translocation occurred, Escherichia coli were cultured from the MLNs. There were no histological changes in the mucosal samples of the control animals. In the CBD-ligated rats, hyperemia, vacuolization, reduction of goblet cells, decreased mitotic activity, and infiltration by lymphocytes and polymorphonuclear leukocytes (PMNLs) were detected. Cases in which translocation occurred were significantly associated with decreased mitotic activity in the colon (r = -0.5, P < 0.01) and higher infiltration by PMNLs in the ileum (r = -0.62, P < 0.05). CONCLUSION: Obstructive jaundice in a rat model predisposes to bacterial translocation. This suggests a mechanism whereby jaundiced patients are susceptible to septic complication.

Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is the most common type of primary glomerular disease in adults worldwide. Several studies have reported that galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgAN.MethodsThirty-five patients with IgAN diagnosed with renal biopsy for the first time served as the experimental group, who were hospitalized in our department. Twenty normal healthy cases in the physical examination center of our hospital served as the control group. Then the levels of Gd-IgA1 in serum and urine, and intestinal mucosal barrier injury indexes [diamine oxidase (DAO), serum soluble intercellular adhesion molecule-1 (sICAM-1), D-lactate (D-LAC), and lipopolysaccharide (LPS)] and inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] in the serum samples were detected. Fecal samples were collected to detect intestinal microbiota using 16 s rDNA sequencing. Then, we assessed possible correlations among clinical and laboratory findings.ResultsIn patients with IgAN, the levels of Gd-IgA1 both in the serum and urine were higher than that of the healthy control. Furthermore, urine Gd-IgA1 level was positively correlated with the serum creatinine level, 24 h urine protein, and M, S, and T parameters in the Oxford classification. ROC curve analysis showed that urine Gd-IgA1 has a greater diagnostic value (AUC = 0.9714, 95% CI, 0.932-1; P < 0.0001) for IgAN. The best cutoff value for urine Gd-IgA1 was 0.745 ng·l/ml·μmol (sensitivity, 94%; specificity, 95%). The intestinal mucosal barrier damage indexes (DAO, sICAM-1, D-LAC, and LPS) were increased in the patients with IgAN, which were positively correlated with Gd-IgA1 levels (P < 0.05) both in serum and urine. The levels of inflammatory factors in the patients with IgAN were increased. 16 s rDNA analysis showed that the intestinal microbiota in these patients was disordered compared to that observed in the healthy subjects. Actinobacteria, Bifidobacterium, Blautia, Bifidobacteriaceae, and Bifidobacteriales were decreased and Shigella was increased in IgAN. The decreased populations of these flora were negatively and significantly correlated with urine Gd-IgA1 and the levels of DAO, sICAM-1, D-LAC, and LPS.ConclusionThe urine Gd-IgA1 levels may be a non-invasive biological marker for evaluating kidney injury in IgAN. Gut flora dysbiosis and intestinal barrier dysfunction may be involved in Gd-IgA1 expression.

Project description:BackgroundGut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.MethodsWe investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.FindingsIn human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.InterpretationOur results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.

Dataset Information

Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction.

Publications

Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets