A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice

2008 ◽  
Vol 104 (1) ◽  
pp. 157-169 ◽  
Author(s):  
Athanasius F. M. Marée ◽  
Mitsuhiro Komba ◽  
Diane T. Finegood ◽  
Leah Edelstein-Keshet
Keyword(s):  
Time Course ◽  
Nod Mice ◽  
Mouse Strains ◽  
Apoptotic Cells ◽  
Time Data ◽  
Feeding Experiments ◽  
Long Time ◽  
Kinetics Of Uptake

Macrophages play an important role in clearing apoptotic debris from tissue. Defective or reduced clearance, seen, for instance, in non-obese diabetic (NOD) mice, has been correlated with initiation of autoimmune (Type 1) diabetes (T1D) (O'Brien BA, Huang Y, Geng X, Dutz JP, Finegood DT. Diabetes 51: 2481–2488, 2002). To validate such a link, it is essential to quantify the reduced clearance (for example, by comparison to BALB/c control mice) and to determine which elements of that clearance are impaired. Recently, we fit data for the time course of in vitro macrophage feeding experiments to basic models of macrophage clearance dynamics, thus quantifying kinetics of uptake and digestion of apoptotic cells in both mouse strains (Marée AFM, Komba M, Dyck C, Łabeçki M, Finegood DT, Edelstein-Keshet L. J Theor Biol 233: 533–551, 2005). In the cycle of modeling and experimental investigation, we identified the importance of 1) measuring short-, intermediate-, and long-time data (to increase the accuracy of parameter fits), and 2) designing experiments with distinct observable regimes, including engulfment-only and digestion-only phases. Here, we report on new results from experiments so designed. In comparing macrophages from the two strains, we find that NOD macrophage engulfment of apoptotic cells is 5.5 times slower than BALB/c controls. Significantly, our new data demonstrate that digestion is at least two times slower in NOD, in contrast with previous conclusions. Moreover, new data enable us to detect an acceleration in engulfment (after the first engulfment) in both strains, but much smaller in NOD macrophages.

scholarly journals A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Luiza A. Castro-Jorge ◽  
Carla D. Pretto ◽  
Asa B. Smith ◽  
Oded Foreman ◽  
Kelly E. Carnahan ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Time Course ◽  
Interleukin 1 ◽  
Adenovirus Type ◽  
Mouse Strains ◽  
Complex Nature ◽  
Type I ◽  
Viral Loads ◽  
The Brain

ABSTRACT Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 −/− mice). Il1r1 −/− mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard −/− mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 −/− mice). Pycard −/− and Unc93b1 −/− mice showed lower survival (similar to Il1r1 −/− mice) than control mice but, unlike Il1r1 −/− mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 −/− mice had a very different inflammatory profile from infected Il1r1 −/− and Pycard −/− mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 −/− mice. A time course of infection of control and Il1r1 −/− mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation. IMPORTANCE The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.

scholarly journals Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the “Nonlethal” Plasmodium yoelii 17XNL Malaria Protozoan

2016 ◽  
Vol 2016 ◽  
pp. 1-9
Author(s):  
Mirian Mendoza ◽  
Luis Pow Sang ◽  
Qi Qiu ◽  
Sofia Casares ◽  
Teodor-D. Brumeanu
Keyword(s):  
B Cell ◽  
Nod Mice ◽  
Treg Cells ◽  
Plasmodium Yoelii ◽  
Mouse Strains ◽  
Nonobese Diabetic ◽  
Blood Stage Infection ◽  
Protective Antibodies ◽  
Antibody Secretion

Background. Plasmodium yoelii 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-Ab/I-Enull) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of P. yoelii 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and self-cure the P. yoelii 17XNL infection. Prediabetic NOD mice could not mount a protective antibody response to the P. yoelii 17XNL-infected red blood cells (iRBCs), and they all succumbed shortly after infection. Our data suggest that the lack of anti-P. yoelii 17XNL-iRBCs protective antibodies in NOD mice is a result of parasite-induced, Foxp3+ T regulatory (Treg) cells able to suppress the parasite-specific antibody secretion. Conclusions. The NOD mouse model may help in identifying new mechanisms of B-cell evasion by malaria parasites. It may also serve as a more accurate tool for testing antimalaria therapeutics due to the lack of interference with a preexistent self-curing mechanism present in other mouse strains.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Modulation of Cytokine Profiles by the Mycoplasma SuperantigenMycoplasma arthritidis Mitogen Parallels Susceptibility to Arthritis Induced by M. arthritidis

2000 ◽  
Vol 68 (3) ◽  
pp. 1142-1149 ◽  
Author(s):  
Hong-Hua Mu ◽  
Allen D. Sawitzke ◽  
Barry C. Cole
Keyword(s):  
Interleukin 12 ◽  
Mouse Strains ◽  
Mild Disease ◽  
Cytokine Profiles ◽  
C Cell ◽  
Severe Arthritis

ABSTRACT Mycoplasma arthritidis mitogen (MAM) is a potent superantigen secreted by M. arthritidis, an agent of murine arthritis. Here we compare the abilities of MAM to induce a panel of cytokines in vitro and in vivo in BALB/c and C3H/HeJ mouse strains that differ in susceptibility to mycoplasmal arthritis. Splenocytes from both mouse strains produced high levels of all cytokines by 24 h following in vitro exposure to MAM. No differences in cytokine profiles were seen irrespective of the MAM dose. However, there were striking differences in cytokine profiles present in supernatants of splenocytes that had been collected from mice after intravenous (i.v.) injection of MAM and subsequently rechallenged with MAM in vitro. Splenocytes collected 24 and 72 h after i.v. injection of MAM and challenged in vitro with MAM showed the most marked divergence in the secreted cytokines. Type 1 cytokines were markedly elevated in C3H/HeJ cell supernatants, whereas they were depressed or remained low in BALB/c cell supernatants. In contrast, the levels of type 2 cytokines were all greatly increased in BALB/c cell cultures but were decreased or remained low in C3H/HeJ supernatants. Interleukin-12 mRNA and protein was also markedly elevated in C3H/HeJ mice, as were the levels of immunoglobulin G2a. The data indicate a major skewing in cytokine profiles to a type 1 inflammatory response in C3H/HeJ mice but to a protective type 2 response in BALB/c mice. These cytokine changes appear to be associated with the severe arthritis in C3H/HeJ mice following injection of M. arthritidis in comparison to the mild disease seen in injected BALB/c mice.

11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

2017 ◽  
Vol 49 (09) ◽  
pp. 693-700 ◽  
Author(s):  
Ahmed Shehata ◽  
Leticia Quintanilla-Fend ◽  
Sabrina Bettio ◽  
Zahra Kamyabi-Moghaddam ◽  
Ursula Kohlhofer ◽  
...  
Keyword(s):  
Animal Model ◽  
Type 1 Diabetes ◽  
Body Weight ◽  
Pancreatic Islets ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Apoptotic Cells ◽  
Boswellic Acid ◽  
Human Type 1 Diabetes

Abstract11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.

Effect of external Ca2+ concentration on stretch-augmented natriuretic peptide secretion by rat atria

1991 ◽  
Vol 260 (4) ◽  
pp. C756-C762 ◽  
Author(s):  
E. Page ◽  
J. Upshaw-Earley ◽  
G. E. Goings ◽  
D. A. Hanck
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Natriuretic Peptide ◽  
Time Course ◽  
Rate Coefficient ◽  
Time Dependent ◽  
Dependent Manner ◽  
Dependent Inactivation ◽  
Long Time ◽  
Peptide Secretion

An in vitro noncontracting rat atrial preparation stretched at 37 degrees C by a distending pressure of 5.1 mmHg was used to examine effects of external Ca2+ concentration ([Ca2+]out, 0.05-3.0 mM) on secretion of immunoreactive atrial natriuretic peptide (ANP) in presence of saxitoxin (STX) and in presence or absence of ryanodine. Under these conditions, the time course of the amount (y) of ANP secreted per milligram dry atrium during 44 min could be approximated by a rate coefficient (k) according to the relation y = s[1 - e(-kt)], where s is the maximal amount secreted after a long time (t). Although k, the rate coefficient for stretch-augmented secretion, increased significantly as [Ca2+]out was raised, secretion inactivated progressively in a time- and [Ca2+]out-dependent manner. This time-dependent decrease was not prevented by ryanodine. We conclude that a component of ANP secreted by quiescent atria in vitro is positively modulated by [Ca2+]out and does not require ryanodine-sensitive Ca2+ release from sarcoplasmic reticulum. The [Ca2+]out-sensitive processes underlying time-dependent inactivation of secretion remain undetermined.

scholarly journals Animal models of Graves' disease

2000 ◽  
pp. 1-8 ◽  
Author(s):  
M Ludgate
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Nod Mice ◽  
Autoimmune Response ◽  
Mouse Strains ◽  
Graves Disease ◽  
Genetic Immunisation

Graves' disease (GD) is an autoimmune condition in which goitre and hyperthyroidism are induced by thyroid stimulating antibodies (TSAB) which mimic the action of thyrotrophin (TSH). The target of the autoimmune response is the thyrotrophin receptor (TSHR) and, since its cloning, a number of differing approaches have been adopted in an attempt to develop an animal model of GD. Methods in which synthetic peptides or fragments of the receptor produced in bacteria or insect cells have been injected into animals together with immunological adjuvants have had only limited success in inducing some of the signs and symptoms of GD. Genetic immunisation resulted in thyroiditis in the majority, but TSAB formation in only a minority, of treated inbred mice. Transfer of receptor in vitro primed T cells to syngeneic naive recipients, with priming either using a bacterial fusion protein or genetic immunisation, induced destructive thyroiditis in non-obese diabetic (NOD) mice but lymphocytic thyroiditis in BALBc mice. Furthermore, the orbits of 17/22 of the BALBc animals, but not the NOD animals, with thyroiditis had orbital changes similar to those seen in thyroid eye disease. TSAB and elevated thyroxine levels were induced in AKR/N mice injected with fibroblasts expressing the full length human TSHR and murine major histocompatibility complex (MHC) class II homologous to the recipient mice. No thyroiditis was induced but preliminary results from a different group using the same protocol suggest that receptor autoantibodies and thyroid dysfunction could be transferred using T cells primed in vitro with the receptor and MHC-II expressing cells. The majority of the studies described above have studied inbred mouse strains. In a novel departure, the NMR outbred strain has been treated by genetic immunisation with very promising results, including the induction of increased thyroxine levels in 4/30 female mice, accompanied by TSAB in addition to thyroiditis, and with signs of hyperactivity and orbital pathology. This review discusses the various protocols together with the information regarding the pathogenesis of GD which each has contributed, and concludes with an evaluation of how close we are to mimicking this polygenic, multifactorial disease.

Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?

2006 ◽  
Vol 364 (1842) ◽  
pp. 1267-1282 ◽  
Author(s):  
Athanasius F.M Marée ◽  
Richard Kublik ◽  
Diane T Finegood ◽  
Leah Edelstein-Keshet
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Apoptotic Cells ◽  
Newborn Mice ◽  
Macrophage Phagocytosis ◽  
Disease Occurrence ◽  
Health And Disease ◽  
The Difference ◽  
Parameter Values

A wave of apoptosis (programmed cell death) occurs normally in pancreatic β-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al . 1999 Diabetes 48 , 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.

scholarly journals Activation of HSD11B1 in the bovine cumulus-oocyte complex during IVM and IVF

2019 ◽  
Vol 8 (7) ◽  
pp. 1029-1039 ◽  
Author(s):  
Masafumi Tetsuka ◽  
Misato Tanakadate
Keyword(s):  
Enzyme Activity ◽  
Time Course ◽  
Cumulus Expansion ◽  
Pge2 Synthesis ◽  
Cumulus Oocyte Complex ◽  
Expression Of Genes ◽  
Key Events ◽  
Glucocorticoid Metabolism

The bovine cumulus-oocyte complex (COC) is capable of converting cortisone, an inert glucocorticoid to active cortisol. This mechanism is mediated by 11β-hydroxysteroid oxidoreductase type 1 (HSD11B1), whose expression dramatically increases in the mature COC. In this study, we investigate the time course expression of HSD11B1 and the enzyme activity in the bovine COC undergoing maturation and fertilization in relation to key events taking place in the COC. Bovine COCs were subjected to in vitro maturation (IVM) and fertilization (IVF). The activities of HSD11B1 and HSD11B2, which mediates the opposite reaction, were measured using a radiometric conversion assay. In parallel studies, cumulus expansion, P4 production and the expression of genes associated with ovulation were measured. The reductive activity of HSD11B1 increased in the latter half of IVM and remained high during IVF, whereas the oxidative activity of HSD11B2 remained unchanged over both periods. Consequently, the net glucocorticoid metabolism in the bovine COC shifted from inactivation to activation around the time of ovulation and fertilization. The increase in HSD11B1 expression lagged behind that of P4 increase and cumulus expansion but ahead of the expressions of genes responsible for PGE2 synthesis. The reductive activity of HSD11B1 was well correlated with the cumulus expansion rate. This outcome indicates that the ability of the cumulus to activate glucocorticoids is related to its ability to synthesize hyaluronan. These results also indicate that the activation of HSD11B1 is an integral part of the sequential events taking place at the ovulation and fertilization in the bovine COC.

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