Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis

Garay-Malpartida, Humberto Miguel; Mourão, Roberta F; Mantovani, Marta Sílvia Maria; Santos, Icaro A; Sogayar, Mari Cleide; Goldberg, Anna Carla

doi:10.1186/1471-2172-12-18

Cited by 81 publications

(76 citation statements)

References 36 publications

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“…Both CXCR3 and TLR4 are expressed on beta cells [46,47] and subsets of NK cells [45,48], and gliadin is known to interact with both receptors [47,49]. Interestingly, a recent study has shown that amylase/trypsin inhibitor family members present in the ω-gliadin fraction are able to induce strong innate responses in human and murine macrophages, monocytes, and DCs via TLR4 [49], through a mechanism that could potentially induce IFN-γ secretion from NK cells [45].…”

Section: Discussionmentioning

confidence: 99%

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-γ secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a + NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46 + cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice.Keywords: C56BL/6 mice r Gliadin r Gluten r NK cells r NOD mice r Type 1 diabetes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDietary gluten is the initiating factor in the development of celiac disease (CD), however, an association between CD and type 1 diabetes (T1D) has been established. A gluten-free (GF) diet has been shown to have a protective effect against the development of T1D. It has been demonstrated that a GF diet in nonobese diabetic (NOD) mice reduces diabetes incidence from 64 to 15% [1], and similar results have been obtained with biobreeding rats [2]. Increased intestinal permeability occurs prior to the onset of T1D in both spontaneous animal models and human disease [3,4]. Patients with both CD and T1D diseases carry high-risk HLA alleles [5], and approximately 10% of T1D patients have anCorrespondence: Jesper Larsen e-mail: jelars@gmail.com increased prevalence of CD [6]. Moreover, T1D rarely develops after diagnosed CD, which may be because of the protective effect of a GF diet [7]. A recently published case report describes a boy with T1D who was able to maintain a low fasting blood glucose level without insulin therapy for more than 20 months after the time of diagnosis by adhering to a GF diet [8]. Lately, it has also been suggested that a family of gluten proteins known as gliadins may contribute directly to beta-cell hyperactivity, as enzymatically digested gliadin and a 33-mer gliadin fragment increase insulin secretion from beta cells by affecting the K ATP channel current [9]. This process could induce increased Ag expression of the beta-cell surface and prevent beta-cell rest [10]. Gliadin has been shown to stimulate several components of the adaptive immune system, such as Treg cells, Th17 cells, and DCs [11,12]. Gliadin fragments have also been shown to stimulate TLR4 a...

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Section: Discussionmentioning

confidence: 99%

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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“…Although we have observed that HERV-W-Env is expressed in the pancreas by acinar cells surrounding β islets (Figure 1D), the concentration of HERV-W-Env to which the β cells are exposed in the pancreas in vivo can only be estimated to be locally elevated. Notably, a decrease in human β cell viability has already been described upon TLR4 activation after exposure to LPS (42).…”

Section: Discussionmentioning

confidence: 99%

“…The underlying mechanism of this inhibition requires further investigations, though it has already been described that HERV-W-Env exerts its pathogenic effects through an interaction with the TLR4 receptor (35,36). From a T1D perspective, this mechanism appears relevant, as TLR4 is expressed by β cells (42)(43)(44). Moreover, the inhibition of insulin secretion following TLR4 stimulation has already been observed in human, rat, and mouse pancreatic β cells by using lipopolysaccharide (LPS), the prototypical ligand of TLR4 (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…From a T1D perspective, this mechanism appears relevant, as TLR4 is expressed by β cells (42)(43)(44). Moreover, the inhibition of insulin secretion following TLR4 stimulation has already been observed in human, rat, and mouse pancreatic β cells by using lipopolysaccharide (LPS), the prototypical ligand of TLR4 (42,43). Inhibition appeared related to the repression of key transcription factors for β cell functions, PDX-1 and Maf-A, in a TLR4-dependent manner and via NF-κB signaling pathway (43).…”

Section: Discussionmentioning

confidence: 99%

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An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

Levet¹,

Médina²,

Joanou³

et al. 2017

JCI Insight

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“…Indeed there is an increase in the level of LPS in the circulation of those subjects and a low-grade endotoxemia, which are believed to play a role in the onset of the metabolic disorders (1). Pancreatic beta cells express significant levels of TLR4 which make them sensitive to the effect of LPS (10,14,40). Circulating LPS binding to TLR4 leads to activation of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-B), p38 mitogen-activated protein kinases (p38 MAPK), activator protein 1 (AP-1), and interferon-inducible inflammatory gene expression (1,14).…”

Section: Discussionmentioning

confidence: 99%

Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process

Ghosal

Sekar

Said

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ghosal A, Sekar TV, Said HM. Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharidesensitive carrier-mediated process. Am J Physiol Gastrointest Liver Physiol 307: G365-G373, 2014. First published June 5, 2014; doi:10.1152/ajpgi.00157.2014.-Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na ϩ -dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid and lipoate; the process is also saturable as a function of concentration (apparent K m ϭ 22.24 Ϯ 5.5 M). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline-inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na ϩ -dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4-mediated process and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS.biotin; pancreatic beta cells; biotin uptake mechanism; transport regulation THE WATER-SOLUBLE VITAMIN BIOTIN, also known as vitamin B7 or vitamin H, is required for normal cellular functions, growth, and development. Biotin acts as a cofactor (as a carboxyl carrier) for five carboxylases that catalyze indispensable steps in intermediate metabolism including gluconeogenesis and fatty acid metabolism (reviewed in Refs. 34, 35). Emerging evidences also point to a role for biotin in normal immune function and in the regulation of gene expression (reviewed in Refs. 24,29). In reference to the latter, biotin status has been shown to influence the expression of more than 2,000 human genes, at both the transcriptional and post-transcriptional levels (3, 30, 44). The affected genes include those that are critical for maintaining the differentiated phenotype of pancreatic beta cells, preservation of their mass (i.e., their proportion), and for insulin secretion (3,30,38,44). In reference to the latter, the vitamin has been shown to increases the expression of pancreatic and duodenal homeobox 1 (Pdx-1) (44), a critical transcri...

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Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis

Cited by 81 publications

References 36 publications

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process

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