scholarly journals The role of the P2X7 nucleotide receptor in salivary gland inflammation

2017 ◽  
Author(s):  
◽  
Mahmoud G. Khalafalla
Keyword(s):  
Salivary Gland ◽  
Epithelial Cells ◽  
Secretory Function ◽  
Tgf Beta ◽  
Nucleotide Receptor ◽  
Saliva Secretion ◽  
Duct Ligation ◽  
P2x7r Activation

Salivary gland inflammation is a hallmark of Sjogren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration and the consequent impairment of the salivary gland and loss of saliva secretion, predominantly in women. The current therapeutic management of SS is relatively ineffective and does not address the underlying inflammatory processes contributing to the pathology of SS. In this study, two novel therapeutic approaches were evaluated to limit salivary gland inflammation and improve secretory function, i.e., antagonism of the P2X7 nucleotide receptor (P2X7R), which prevents salivary gland inflammation and activation of the P2Y[subscript2] nucleotide receptor (P2Y[subscript2]R) which stimulates the regeneration of damaged salivary glands. The P2X7R is an ATP-gated non-selective cation channel that regulates inflammatory responses in cells and tissues, including salivary gland epithelium. The P2X7R contributes to the pathology of a variety of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In immune cells, P2X7R activation induces the production of pro-inflammatory cytokines, including IL-1[beta] and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. This study (Chapter II) sheds light on the role of the P2X7R in salivary gland inflammation and hyposalivation. Our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1[beta], responses that are absent in SMG cells isolated from mice devoid of P2X7Rs (P2X7R[superscript-/-]). P2X7R-mediated IL-1[beta] release in SMG epithelial cells is dependent on downhill transmembrane Na[superscript+] and/or K[superscript+] fluxes, the activation of heat shock protein 90 (HSP90), a protein required for the activation and stabilization of the NLRP3 inflammasome, and the generation of mitochondrial ROS. In vivo administration of the P2X7R antagonist A438079 in the CD28[superscript-/-], IFN[superscript][superscript-/-], NOD.H-2[superscripth4] mouse model of salivary gland exocrinopathy ameliorated salivary gland inflammation and enhanced carbachol-induced saliva secretion. These findings demonstrate that P2X7R antagonism in vivo represents a promising therapeutic strategy to limit salivary gland inflammation and improve secretory function. The P2Y[subscript2]R, a G protein-coupled receptor equipotently activated by ATP and UTP, is upregulated in a variety of tissues, including salivary gland epithelium, in response to injury or stress and is proposed to play a role in tissue regeneration. The results indicated that P2Y2R activation with UTP enhances the migration, aggregation and self-organization of dispersed salivary epithelial cells forming spheres that display characteristics similar to differentiated acini in salivary glands. One of the consequences of the chronic inflammatory disease SS is the fibrosis of the salivary gland. The role of transforming growth factor- [beta] (TGF-[beta]) is well established in the fibrosis and regeneration of various organs, including the liver, lung and kidney. In this study, results with a submandibular gland (SMG) duct ligation-induced mouse model of fibrosis indicated that 7 days of SMG duct ligation resulted in upregulation of TGF-β signaling components which correlated with the upregulation of the fibrosis markers collagen 1 and fibronectin, responses that were inhibited by administration of the TGF-[beta] receptor 1 inhibitors. These results suggest that TGF-[beta] signaling contributes to duct ligation-induced changes in salivary epithelium that correlate with glandular fibrosis.

Flagellin induces innate immune genes in bronchial epithelial cells in vivo: Role of TET2

2021 ◽  
Author(s):  
Wanhai Qin ◽  
Xanthe Brands ◽  
Cornelis Veer ◽  
Alex F. Vos ◽  
Brendon P. Scicluna ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Innate Immune ◽  
Bronchial Epithelial ◽  
Immune Genes ◽  
Innate Immune Genes

scholarly journals Choline Acetyltransferase Induces the Functional Regeneration of the Salivary Gland in Aging SAMP1/Kl -/- Mice

2021 ◽  
Vol 22 (1) ◽  
pp. 404
Author(s):  
Nguyen Khanh Toan ◽  
Nguyen Chi Tai ◽  
Soo-A Kim ◽  
Sang-Gun Ahn
Keyword(s):  
Salivary Gland ◽  
Choline Acetyltransferase ◽  
Salivary Flow ◽  
Salivary Secretion ◽  
Functional Markers ◽  
Tooth Structure ◽  
Saliva Secretion ◽  
Gland Function ◽  
The Impact

Salivary gland dysfunction induces salivary flow reduction and a dry mouth, and commonly involves oral dysfunction, tooth structure deterioration, and infection through reduced salivation. This study aimed to investigate the impact of aging on the salivary gland by a metabolomics approach in an extensive aging mouse model, SAMP1/Klotho -/- mice. We found that the salivary secretion of SAMP1/Klotho -/- mice was dramatically decreased compared with that of SAMP1/Klotho WT (+/+) mice. Metabolomics profiling analysis showed that the level of acetylcholine was significantly decreased in SAMP1/Klotho -/- mice, although the corresponding levels of acetylcholine precursors, acetyl-CoA and choline, increased. Interestingly, the mRNA and protein expression of choline acetyltransferase (ChAT), which is responsible for catalyzing acetylcholine synthesis, was significantly decreased in SAMP1/Klotho -/- mice. The overexpression of ChAT induced the expression of salivary gland functional markers (α–amylase, ZO-1, and Aqua5) in primary cultured salivary gland cells from SAMP1/Klotho +/+ and -/- mice. In an in vivo study, adeno-associated virus (AAV)-ChAT transduction significantly increased saliva secretion compared with the control in SAMP1/Klotho -/- mice. These results suggest that the dysfunction in acetylcholine biosynthesis induced by ChAT reduction may cause impaired salivary gland function

scholarly journals Expression of lysophosphatidic acid receptor 5 is necessary for the regulation of intestinal Na+/H+ exchanger 3 by lysophosphatidic acid in vivo

2018 ◽  
Vol 315 (4) ◽  
pp. G433-G442 ◽  
Author(s):  
Kayte A. Jenkin ◽  
Peijian He ◽  
C. Chris Yun
Keyword(s):  
Epithelial Cells ◽  
Lysophosphatidic Acid ◽  
Direct Evidence ◽  
Intestinal Epithelial Cells ◽  
Regulatory Role ◽  
Intestinal Epithelial ◽  
Fluid Absorption ◽  
Wild Type

Lysophosphatidic acid (LPA) is a bioactive lipid molecule, which regulates a broad range of pathophysiological processes. Recent studies have demonstrated that LPA modulates electrolyte flux in the intestine, and its potential as an antidiarrheal agent has been suggested. Of six LPA receptors, LPA5 is highly expressed in the intestine. Recent studies by our group have demonstrated activation of Na+/H+ exchanger 3 (NHE3) by LPA5. However, much of what has been elucidated was achieved using colonic cell lines that were transfected to express LPA5. In the current study, we engineered a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC, and investigated the role of LPA5 in NHE3 regulation and fluid absorption in vivo. The intestine of Lpar5ΔIEC mice appeared morphologically normal, and the stool frequency and fecal water content were unchanged compared with wild-type mice. Basal rates of NHE3 activity and fluid absorption and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5. NHE3 activation involves trafficking of NHE3 from the terminal web to microvilli, and this mobilization of NHE3 by LPA was abolished in Lpar5ΔIEC mice. Dysregulation of NHE3 was specific to LPA, and insulin and cholera toxin were able to stimulate and inhibit NHE3, respectively, in both wild-type and Lpar5ΔIEC mice. The current study for the first time demonstrates the necessity of LPA5 in LPA-mediated stimulation of NHE3 in vivo. NEW & NOTEWORTHY This study is the first to assess the role of LPA5 in NHE3 regulation and fluid absorption in vivo using a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC. Basal rates of NHE3 activity and fluid absorption, and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5.

scholarly journals C3 Promotes Clearance of Klebsiella pneumoniae by A549 Epithelial Cells

2004 ◽  
Vol 72 (3) ◽  
pp. 1767-1774 ◽  
Author(s):  
Beatriz de Astorza ◽  
Guadalupe Cortés ◽  
Catalina Crespí ◽  
Carles Saus ◽  
José María Rojo ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Klebsiella Pneumoniae ◽  
Alveolar Epithelial Cells ◽  
Clinical Isolates ◽  
Complement Components ◽  
Innate Defense ◽  
Alveolar Epithelial

ABSTRACT The airway epithelium represents a primary site for contact between microbes and their hosts. To assess the role of complement in this event, we studied the interaction between the A549 cell line derived from human alveolar epithelial cells and a major nosocomial pathogen, Klebsiella pneumoniae, in the presence of serum. In vitro, we found that C3 opsonization of poorly encapsulated K. pneumoniae clinical isolates and an unencapsulated mutant enhanced dramatically bacterial internalization by A549 epithelial cells compared to highly encapsulated clinical isolates. Local complement components (either present in the human bronchoalveolar lavage or produced by A549 epithelial cells) were sufficient to opsonize K. pneumoniae. CD46 could competitively inhibit the internalization of K. pneumoniae by the epithelial cells, suggesting that CD46 is a receptor for the binding of complement-opsonized K. pneumoniae to these cells. We observed that poorly encapsulated strains appeared into the alveolar epithelial cells in vivo but that (by contrast) they were completely avirulent in a mouse model of pneumonia compared to the highly encapsulated strains. Our results show that bacterial opsonization by complement enhances the internalization of the avirulent microorganisms by nonphagocytic cells such as A549 epithelial cells and allows an efficient innate defense.

Cellular Samurai: katanin and the severing of microtubules

2000 ◽  
Vol 113 (16) ◽  
pp. 2821-2827 ◽  
Author(s):  
L. Quarmby
Keyword(s):  
Epithelial Cells ◽  
Essential Role ◽  
Aaa Atpase ◽  
C Elegans ◽  
Microtubule Severing ◽  
Biochemical Studies ◽  
New Evidence

Recent biochemical studies of the AAA ATPase, katanin, provide a foundation for understanding how microtubules might be severed along their length. These in vitro studies are complemented by a series of recent reports of direct in vivo observation of microtubule breakage, which indicate that the in vitro phenomenon of catalysed microtubule severing is likely to be physiological. There is also new evidence that microtubule severing by katanin is important for the production of non-centrosomal microtubules in cells such as neurons and epithelial cells. Although it has been difficult to establish the role of katanin in mitosis, new genetic evidence indicates that a katanin-like protein, MEI-1, plays an essential role in meiosis in C. elegans. Finally, new proteins involved in the severing of axonemal microtubules have been discovered in the deflagellation system of Chlamydomonas.

scholarly journals Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids

2020 ◽  
Vol 13 (9) ◽  
pp. dmm045054 ◽  
Author(s):  
Shohei Yoshimoto ◽  
Junko Yoshizumi ◽  
Hiromasa Anzai ◽  
Koichiro Morishita ◽  
Kazuhiko Okamura ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Fungal Infections ◽  
Disease Model ◽  
Good Health ◽  
Functional Changes ◽  
Human Salivary Gland ◽  
Saliva Secretion ◽  
Tnf Α

ABSTRACTHyposalivation and xerostomia are the cause of several morbidities, such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and for keeping good health. Several strategies for restoring salivary gland function have been reported, from different points of view, based on the use of salivary-gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids that mimic in vivo salivary glands. In this study, we clarified that inhibition of activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary-gland-derived organoids, and demonstrated the usefulness of such organoids as an inflammatory disease model. In inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, also known as TNF) are upregulated, but their function is still unclear. In our established human salivary-gland-derived organoid culture system, we successfully induced organoid swelling by stimulation with carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-α. From these results, we could clarify the inhibitory function of TNF-α on saliva secretion in vitro. Thus, our established human salivary-gland-derived organoids would be useful for in vitro analyses of the morphological and functional changes involved in salivary gland dysfunctions in several research fields, such as pathobiology, inflammation and regenerative medicine.This article has an associated First Person interview with the first author of the paper.

scholarly journals Hyperinsulinemia, But Not Other Factors Associated with Insulin Resistance, Acutely Enhances Colorectal Epithelial Proliferation in Vivo

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1830-1837 ◽  
Author(s):  
Thien T. Tran ◽  
Dinaz Naigamwalla ◽  
Andrei I. Oprescu ◽  
Loretta Lam ◽  
Gail McKeown-Eyssen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Epithelial Cells ◽  
Dependent Manner ◽  
Epithelial Proliferation ◽  
Euglycemic Clamp ◽  
The Individual ◽  
Dose Dependent ◽  
Circulating Levels

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.

scholarly journals Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

2018 ◽  
Vol 97 (11) ◽  
pp. 1252-1259 ◽  
Author(s):  
J.J. Varghese ◽  
I.L. Schmale ◽  
D. Mickelsen ◽  
M.E. Hansen ◽  
S.D. Newlands ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Side Effects ◽  
Cellular Level ◽  
Systemic Administration ◽  
Therapeutic Window ◽  
Saliva Secretion ◽  
Life Issues ◽  
Localized Delivery ◽  
Gland Function

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration–approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

scholarly journals Role of LPA and the Hippo pathway on apoptosis in salivary gland epithelial cells

2014 ◽  
Vol 46 (12) ◽  
pp. e125-e125 ◽  
Author(s):  
Sung-Min Hwang ◽  
MeiHong Jin ◽  
Yong Hwan Shin ◽  
Seul Ki Choi ◽  
Eun Namkoong ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Epithelial Cells ◽  
Hippo Pathway ◽  
Salivary Gland Epithelial Cells ◽  
The Hippo Pathway

scholarly journals Morphogenic Effects of Ezrin Require a Phosphorylation-Induced Transition from Oligomers to Monomers at the Plasma Membrane

2000 ◽  
Vol 150 (1) ◽  
pp. 193-204 ◽  
Author(s):  
Alexis Gautreau ◽  
Daniel Louvard ◽  
Monique Arpin
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Wild Type ◽  
Erm Proteins ◽  
Threonine Residue ◽  
Phosphorylation Event ◽  
Membrane Bound

ERM (ezrin, radixin, moesin) proteins act as linkers between the plasma membrane and the actin cytoskeleton. An interaction between their NH2- and COOH-terminal domains occurs intramolecularly in closed monomers and intermolecularly in head-to-tail oligomers. In vitro, phosphorylation of a conserved threonine residue (T567 in ezrin) in the COOH-terminal domain of ERM proteins disrupts this interaction. Here, we have analyzed the role of this phosphorylation event in vivo, by deriving stable clones producing wild-type, T567A, and T567D ezrin from LLC-PK1 epithelial cells. We found that T567A ezrin was poorly associated with the cytoskeleton, but was able to form oligomers. In contrast, T567D ezrin was associated with the cytoskeleton, but its distribution was shifted from oligomers to monomers at the membrane. Moreover, production of T567D ezrin induced the formation of lamellipodia, membrane ruffles, and tufts of microvilli. Both T567A and T567D ezrin affected the development of multicellular epithelial structures. Collectively, these results suggest that phosphorylation of ERM proteins on this conserved threonine regulates the transition from membrane-bound oligomers to active monomers, which induce and are part of actin-rich membrane projections.

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