Acceleration of diabetes in young NOD mice with peritoneal macrophages

Shimada, Akira; Takei, Izumi; Maruyama, Taro; Kasuga, Akira; Kasatani, Tomohiro; Watanabe, Kenji; Asaba, Yoshiaki; Ishii, Toshiharu; Tadakuma, Takushi; Habu, Sonoko; Miyazaki, Jun‐ichi; Saruta, Takao

doi:10.1016/0168-8227(94)90022-1

Cited by 12 publications

(9 citation statements)

References 21 publications

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“…In our previous reports, PGE 2 production was significantly suppressed in peritoneal macrophages of cPLA 2 α −/− mice [7]. As the peritoneal macrophages are known to be involved in the development of diabetes in NOD mice [9–11], we investigated the production of PGE 2 by the peritoneal macrophages of cPLA 2 α +/+ , cPLA 2 α +/− , and cPLA 2 α −/− NOD mice at 18 weeks of age. When peritoneal macrophages were stimulated with a Ca 2+ ionophore (A23187) for 30 min or LPS for 8 h, PGE 2 production was markedly lower in the cPLA 2 α −/− NOD mice than in the cPLA 2 α +/+ and cPLA 2 α +/− NOD mice (Fig.…”

Section: Resultsmentioning

confidence: 90%

Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

et al. 2005

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Cytosolic phospholipase A 2 a (cPLA 2 a) plays an important role in arachidonate pathway. To investigate the contribution of cPLA 2 a to autoimmune diabetes, we established non-obese diabetic (NOD) mouse, an excellent model for human type 1 diabetes, deficient in cPLA 2 a. These mice showed severe insulitis and a higher incidence of diabetes. In their macrophages, decreased prostaglandin E 2 (PGE 2 ) induced by cPLA 2 a deficiency, and the increase in production of tumor necrosis factor (TNF)-a were observed. These results suggested that cPLA 2 a plays a protective role in progression of insulitis and development of autoimmune diabetes by suppression of TNF-a production from macrophages.

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Section: Resultsmentioning

confidence: 90%

Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

et al. 2005

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“…In the case of EAE, depletion of peripheral macrophages, or specifically of TNF production by myeloid cells was insufficient to impact the development of auto-antigen specific Th1 cells, but prevented the infiltration of lymphocytes into the CNS parenchyma, and inhibited demyelination and disease3839. In a similar way, peritoneal macrophages were shown to accelerate the disease process in NOD mice40 and as a major source of pro-inflammatory cytokines41 may also regulate cellular infiltration to the pancreas42. Our histological data in both NOD and EAE mice-treated with FhHDM-1, supports a mechanism by which FhHDM-1 regulates the activation of macrophages to consequently reduce the migration of pathogenic immune cells to the site of autoimmunity thereby preventing tissue destruction and subsequent clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

Lund

Greer

Dixit

et al. 2016

Sci Rep

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Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.

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“…A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice Relative to BALB/c (controls), macrophages of NOD mice are identifiably different (16,39), exhibiting abnormal cytokine secretion (2), reduced activation of other immune cells (17,20), and reduced phagocytosis (35). Based on these observations, it has been suggested that defective macrophage clearance of the neonatal wave of ␤-cell apoptosis leads to self-presentation and, subsequently, to T-cell activation (27,40).…”

mentioning

confidence: 99%

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

Marée

Komba²,

Finegood³

et al. 2008

Journal of Applied Physiology

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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.

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Acceleration of diabetes in young NOD mice with peritoneal macrophages

Cited by 12 publications

References 21 publications

Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

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

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Acceleration of diabetes in young NOD mice with peritoneal macrophages

Cited by 12 publications

References 21 publications

Protective role for cytosolic phospholipase A2α in autoimmune diabetes of mice

Protective role for cytosolic phospholipase A2α in autoimmune diabetes of mice

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

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

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Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice