Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells

Stafford, Joshua D.; Yeo, Chay Teng; Corbett, John A.

doi:10.1074/jbc.ra120.015893

Cited by 9 publications

(3 citation statements)

References 73 publications

(112 reference statements)

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“…Therefore, if cytokines were solely damaging to β-cells, we might expect a higher incidence of T1D than currently observed. In support of this hypothesis, cytokines stimulate protective gene expression in β-cells 23 , and, through production of nitric oxide, protect β-cells from apoptosis 26 and viral infection 24 , 25 .…”

Section: Discussionmentioning

confidence: 92%

Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells

et al. 2021

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While exposure to inflammatory cytokines is thought to contribute to pancreatic β-cell damage during diabetes, primarily because cytokine-induced nitric oxide impairs β-cell function and causes cell death with prolonged exposure, we hypothesize that there is a physiological role for cytokine signaling that functions to protect β-cells from a number of environmental stresses. This hypothesis is derived from the knowledge that β-cells are essential for survival even though they have a limited capacity to replicate, yet they are exposed to high cytokine levels during infection as most of the pancreatic blood flow is directed to islets. Here, mouse islets were subjected to single-cell RNA sequencing following 18-hr cytokine exposure. Treatment with IL-1β and IFN-γ leads to expression of inducible nitric oxide synthase (iNOS) mRNA and antiviral and immune-associated genes as well as repression of islet identity factors in a subset of β- and non-β endocrine cells in a nitric oxide-independent manner. Nitric oxide-dependent expression of genes encoding heat shock proteins was observed in both β- and non-β endocrine cells. Interestingly, cells with high expression of heat shock proteins failed to increase antiviral and immune-associated genes, suggesting that nitric oxide may be an internal “off switch” to prevent the negative effects of prolonged cytokine signaling in islet endocrine cells. We found no evidence for pro-apoptotic gene expression following 18-hr cytokine exposure. Our findings suggest that the primary functions of cytokines and nitric oxide are to protect islet endocrine cells from damage, and only when regulation of cytokine signaling is lost does irreversible damage occur.

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Section: Discussionmentioning

confidence: 92%

Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells

et al. 2021

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“…Consistent with this, several viruses have been shown to stimulate cellular metabolism [20][21][22], which prepares the cell to increase ATP demand through viral replication. At the opposite, severe impairment of mitochondrial activity has been shown to impact on viral replication [23] but it remained unexplored how much of interference might be e cient and if it could be related to antiviral properties of a drug in use.…”

Section: Viruses Dependent On Cellular Bioenergeticsmentioning

confidence: 99%

Nitazoxanide controls virus viability through its impact on membrane bioenergetics

Hammad,

Ransy,

Pinson

et al. 2024

Preprint

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Viruses are dependent on cellular energy metabolism for their replication, and the drug nitazoxanide (Alinia) was shown to interfere with both processes. Nitazoxanide is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that mitochondrial uncoupling underlies the antiviral effects of nitazoxanide. Tizoxanide (the active metabolite of nitazoxanide), its derivative RM4848 and the uncoupler CCCP were applied to a virus-releasing cell line to obtain the same increasing levels of mitochondrial uncoupling, hence identical interference with OXPHOS. A decrease in infectious viral particle release was observed and reflected the intensity of interference with OXPHOS, irrespective of the nature of the drug. The antiviral effect was significant although the impact on OXPHOS was modest (≤ 25%), and disappeared when a high concentration (25 mM) of glucose was used to enhance glycolytic generation of ATP. Accordingly, the most likely explanation is that moderate interference with mitochondrial OXPHOS induced rearrangement of ATP use and acquisition of infective properties of the viral particles be highly sensitive to this rearrangement. The antiviral effect of nitazoxanide has been supported by clinical trials, and nitazoxanide is considered a safe drug. However, serious adverse effects of the uncoupler dinitrophenol occurred when used to increase significantly metabolic rate with the purpose of weight loss. In addition, dinitrophenol is known to interfere with mitochondrial ATP transport while we demonstrate that nitazoxanide does not. Taken together, while impairment of mitochondrial bioenergetics is an unwanted drug effect, moderate interference should be considered as a basis for therapeutic efficacy.

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“… 14 , 15 Nitric oxide, by inhibiting mitochondrial oxidation, attenuates viral replication in a β-cell-selective manner, and nitric oxide is a potent inhibitor of insulinoma cell apoptosis. 16 , 17 Importantly the inhibition of mitochondrial oxidation and insulin secretion are completely reversible, and β-cells have efficient mechanisms to repair damaged DNA; it is only prolonged incubations with IL-1β (greater than 36 h in vitro) that lead to irreversible damage. 18–21 Together, these previous studies performed in rodent and human islets support a physiological model in which IL-1β signals to islet endocrine cells to increase the expression of protective, anti-pathogen factors.…”

Section: Introductionmentioning

confidence: 99%

Single Cell RNAseq Analysis of Cytokine-Treated Human Islets: Association of Cellular Stress with Impaired Cytokine Responsiveness

Stancill,

Kasmani,

Cui

et al. 2024

Function

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Pancreatic β-cells are essential for survival, being the only cell type capable of insulin secretion. While they are believed to be vulnerable to damage by inflammatory cytokines such as interleukin-1 beta (IL-1β) and interferon-gamma (IFN-γ), we have recently identified physiological roles for cytokine signaling in rodent β-cells that include the stimulation of antiviral and antimicrobial gene expression and the inhibition of viral replication. In this study, we examine cytokine-stimulated changes in gene expression in human islets using single-cell RNA sequencing. Surprisingly, the global responses of human islets to cytokine exposure were remarkably blunted compared to our previous observations in the mouse. The small population of human islet cells that were cytokine responsive exhibited increased expression of IL-1β-stimulated antiviral guanylate binding proteins, just like in the mouse. Most human islet cells were not responsive to cytokines, and this lack of responsiveness was associated with high expression of genes encoding ribosomal proteins. We further correlated the expression levels of RPL5 with stress response genes, and when expressed at high levels, RPL5 is predictive of failure to respond to cytokines in all endocrine cells. We postulate that donor cause of death and isolation methodologies may contribute to stress of the islet preparation. Our findings indicate that activation of stress responses in human islets limits cytokine-stimulated gene expression, and we urge caution in the evaluation of studies that have examined cytokine-stimulated gene expression in human islets without evaluation of stress-related gene expression.

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Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells

Cited by 9 publications

References 73 publications

Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells

Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells

Nitazoxanide controls virus viability through its impact on membrane bioenergetics

Single Cell RNAseq Analysis of Cytokine-Treated Human Islets: Association of Cellular Stress with Impaired Cytokine Responsiveness

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