A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse

O’Brien, Bronwyn A.; Geng, Xuan; Orteu, Catherine H.; Huang, Yongqian; Ghoreishi, Mehran; Zhang, YiQun; Bush, Jason A.; Li, Gang; Finegood, Diane T.; Dutz, Jan P.

doi:10.1016/j.jaut.2005.11.006

Cited by 103 publications

(70 citation statements)

References 48 publications

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“…Genetic and environmental factors that affect their responses have been linked to the pathogenesis of DMT1, although the exact mechanisms remain unknown (Fan et al 2004;Shultz et al 1995). It has been suggested that deficient internalization and/or clearance of AC by Mfs may be linked to the development of autoimmunity (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). Both AC and pathogens are internalized by phagocytosis, although the cell surface receptors involved in these processes are different.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in Mfs derived from NOD mice, it has been reported that, together with the impaired phagocytosis of AC (O'Brien et al 2006), an abnormal production of IL-12 (Rainbow et al 2008), IL-21 (King et al 2004), and IL-1β (Bouma et al 2005) also occurs. It is important to remark that quantitative and kinetic balance of pro-and antiinflammatory mediators contributes to restoring immunological homeostasis and determines the final outcome of biological processes (Brown et al 2003).…”

Section: Resultsmentioning

confidence: 99%

“…It is well accepted that the initiation and the progression of DMT1 is linked to intrinsic dysfunction in professional phagocytes (i.e., Mfs), which results in a compromised mounting of immune and inflammatory responses (Fan et al 2004;Shultz et al 1995;O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). For example, it has been shown that deficient internalization of AC by Mfs derived from diabetic individuals is accompanied by decreased production of IL-10 and increased secretion of pro-inflammatory cytokines, generating an unusual pro-inflammatory environment in response to AC (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). On the contrary, incubation of DMT1-derived Mfs with pro-inflammatory stimuli has been shown to produce unusually high levels of PGE 2 , which leads to down-regulation of cellular immune activation and therefore a decrease in inflammation (Benhamou et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Vega

Charles

Alexander

2011

Cell Stress and Chaperones

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Diabetes mellitus type 1 (DMT1) is an autoimmune disease characterized by the destruction of insulinproducing cells in the pancreas. Diabetic patients are more susceptible to recurrent and uncontrolled infections, with worse prognoses than in healthy individuals. Macrophages (Mfs) derived from DMT1 individuals have compromised mounting of inflammatory and immune responses. The mechanisms responsible for these alterations remain unknown. It has been shown that the presence of extra-and intracellular heat shock proteins (hsp) positively modulates immune cell function. Using naive Mfs derived from nonobese diabetic (NOD) mice, a well-established mouse model for DMT1, we demonstrate that heat shock (HS) as well as treatment with geldanamycin (GA), significantly improves diabetic Mf activation, resulting in increased phagocytosis and killing of bacteria. Induction of HS did not affect the aberrant NOD-Mf cytokine profile, which is characterized by elevated IL-10 levels and normal tumor necrosis factor alpha. Our observations were consistent at pre-diabetic (normal random blood glucose) and diabetic (random blood glucose greater than 250 mg/dl) stages, suggesting that HS and GA treatment may compensate for intrinsic genetic alterations present in diabetic cells regardless of the stage of the disease. The mechanisms associated to this phenomenon are unknown, but they may likely be associated with the induction of hsp expression, a common factor between HS and GA treatment. Our results may open a new field for non-classical function of hsp and indicate that hsp expression may be used as a part of therapeutic approaches for the treatment of complications associated with DMT1 as well as other autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Vega

Charles

Alexander

2011

Cell Stress and Chaperones

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“…Slowly cleared apoptotic cells may stimulate endosomal TLRs. In the NOD mouse the clearance of apoptotic cells by macrophages is delayed [15,16] and the death of beta cells promotes the activation and proliferation of diabetogenic CTLs [17]. Viruses may also precipitate type 1 diabetes in animal models and in humans [18,19].…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

et al. 2011

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Aims/hypothesis The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8 + T cells. Methods We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8 + T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). Results TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. Conclusions/interpretation TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.

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“…Using a spontaneous type 1 diabetes animal model (Non-Obese Diabetic mouse, NOD mouse), we demonstrated an essential role of HMGB1 in the development of type 1 diabetes [5,6]. Defects in apoptotic β cell clearance have been considered as an important cause of type 1 diabetes [20][21][22][23][24], although the underlying mechanisms remain elusive. To illustrate the importance of HMGB1 in this process, we confirmed that HMGB1 could be passive released by apoptotic β cells, not only by necrotic cells [6].…”

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confidence: 99%

HMGB1 as an Innate Alarmin Promotes Autoimmune Progress: An Essential Role in the Pathogenesis of Type 1 Diabetes

Zhong¹

2015

J Biomol Res Ther

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A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse

Cited by 103 publications

References 48 publications

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

HMGB1 as an Innate Alarmin Promotes Autoimmune Progress: An Essential Role in the Pathogenesis of Type 1 Diabetes

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