Animal Models of Spontaneous Autoimmune Disease

Giarratana, Nadia; Penna, Giuseppe; Adorini, Luciano

doi:10.1007/978-1-59745-395-0_17

Cited by 52 publications

(20 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous reports have shown that most of NOD/ShiLtJ mice become diabetic between 12 and 16 weeks of age, and the development and onset of the type-1 diabetes is accelerated upon PD-L1 blockade3760. We therefore monitored the urine glucose levels in mice during the course of anti-PD-L1 treatment and found that they remained normal in all the mice throughout the experiments.…”

Section: Discussionmentioning

confidence: 92%

Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren’s syndrome in non-obese diabetic mice

Zhou

Jin²,

Kawai

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjögren’s syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-γ in the SMG. Local administration of exogenous IFN-γ to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-γ markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-γ production.

show abstract

Section: Discussionmentioning

confidence: 92%

Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren’s syndrome in non-obese diabetic mice

Zhou

Jin²,

Kawai

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…We then tested whether the development of diabetes in NOD mice, a well-established type 1 diabetes model (26), is preceded by changes in the level of miRNAs in pancreatic islets. In NOD mice, peri-insulitis begins around a few islets 6–8 weeks after birth and characterizes a majority of islets at the age of ∼13–14 weeks (27).…”

Section: Resultsmentioning

confidence: 99%

Involvement of MicroRNAs in the Cytotoxic Effects Exerted by Proinflammatory Cytokines on Pancreatic β-Cells

et al. 2010

View full text Add to dashboard Cite

OBJECTIVEPancreatic β-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated β-cell cytotoxicity.RESEARCH DESIGN AND METHODSWe used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in β-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated β-cell failure by modifying their expression in insulin-secreting MIN6 cells.RESULTSWe found that IL-1β and TNF-α induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1β exposure. Moreover, anti–miR-34a and anti–miR-146a treatment protected MIN6 cells from cytokine-triggered cell death.CONCLUSIONSOur data identify miR-21, miR-34a, and miR-146a as novel players in β-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.

show abstract

“…Because FAS is regulated by insulin in lipogenic tissues (37), we showed that FAS protein was decreased in the hearts of two insulin-deficient models, streptozotocin-treated mice and animals with K ATP -induced neonatal diabetes (17,38), and in the hearts of an insulin-resistant model, db/db mice (Fig. 1, A-C) (39).…”

Section: Cardiac Fas and Generation Of Faskardmentioning

confidence: 95%

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Razani

Zhang

Schulze

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Fatty acid synthase (FAS) promotes energy storage through de novo lipogenesis and participates in signaling by the nuclear receptor PPAR␣ in noncardiac tissues. To determine if de novo lipogenesis is relevant to cardiac physiology, we generated and characterized FAS knockout in the myocardium (FASKard) mice. FASKard mice develop normally, manifest normal resting heart function, and have normal cardiac PPAR␣ signaling as well as fatty acid oxidation. However, they decompensate with stress. Most die within 1 h of transverse aortic constriction, probably due to arrhythmia. Voltage clamp measurements of FASKard cardiomyocytes show hyperactivation of L-type calcium channel current that could not be reversed with palmitate supplementation. Of the classic regulators of this current, Ca 2؉ / calmodulin-dependent protein kinase II (CaMKII) but not protein kinase A signaling is activated in FASKard hearts, and knockdown of FAS in cultured cells activates CaMKII. In addition to being intolerant of the stress of acute pressure, FASKard hearts were also intolerant of the stress of aging, reflected as persistent CaMKII hyperactivation, progression to dilatation, and premature death by ϳ1 year of age. CaMKII signaling appears to be pathogenic in FASKard hearts because inhibition of its signaling in vivo rescues mice from early mortality after transverse aortic constriction. FAS was also increased in two mechanistically distinct mouse models of heart failure and in the hearts of humans with end stage cardiomyopathy. These data implicate a novel relationship between FAS and calcium signaling in the heart and suggest that FAS induction in stressed myocardium represents a compensatory response to protect cardiomyocytes from pathological calcium flux.Storing energy preserves the function of many mammalian tissues during physiological and pathological stress. One of the ways that tissues store energy is through de novo lipogenesis, the synthesis of saturated fatty acids from carbohydrate precursors (1). This process, accomplished by iterative two-carbon additions to a fatty acid chain, is mediated by the multifunctional enzyme FAS 2 (2, 3). Initially relegated to cellular housekeeping, FAS was recently also shown to participate in intracellular signaling. Whole body FAS-deficient embryos die before uterine implantation (4), but liver-specific FAS knock-out mice (5) have decreased expression of fatty acid oxidation genes (classic targets of PPAR␣ signaling) and a phenotype resembling PPAR␣-deficient mice (6). Pharmacological activation of PPAR␣ reverses these features, suggesting that FAS generates an endogenous ligand for PPAR␣, and this FAS-dependent molecule was recently identified as a discrete phosphatidylcholine species (7). FAS also triggers PPAR␣ signaling in the hypothalamus (8) and in macrophages (9), raising the possibility that molecules generated by this enzyme are necessary for activating fatty acid metabolism, even in fatty acid-dependent tissues, such as the heart.Myocardial reliance on fatty acids as an energy source...

show abstract

Animal Models of Spontaneous Autoimmune Disease

Cited by 52 publications

References 151 publications

Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren’s syndrome in non-obese diabetic mice

Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren’s syndrome in non-obese diabetic mice

Involvement of MicroRNAs in the Cytotoxic Effects Exerted by Proinflammatory Cytokines on Pancreatic β-Cells

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Contact Info

Product

Resources

About