Quantifying macrophage defects in type 1 diabetes

Marée, Athanasius F. M.; Komba, Mitsuhiro; Dyck, Cheryl; Łabȩcki, Marek; Finegood, Diane T.; Edelstein‐Keshet, Leah

doi:10.1016/j.jtbi.2004.10.030

Cited by 51 publications

(61 citation statements)

References 20 publications

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“…In agreement with this, induction of hsp in several clinical conditions, such as ischemia/reperfusion, infections, respiratory distress, hemorrhage, and diabetes, has been observed (Donnelly et al 1992;De Maio 1999;Giffard et al 2008;Villar et al 1993). Among these conditions, diabetes and, more specifically, diabetes mellitus type 1 (DMT1) represents an interesting scenario for a potential modulatory effect of hsp, particularly since functional and developmental defects of professional phagocytes have been associated with the initiation and progression of this autoimmune disease (Bagley et al 2008;Hutchings et al 1990;Jun et al 1999;Maree et al 2005;Gordon and Taylor 2005).…”

Section: Introductionmentioning

confidence: 56%

“…The precise mechanism(s) involved in this depressed response remains unclear. Maree et al (2005Maree et al ( , 2008 have suggested that a combination between a low rate of engulfment (phagosome formation) and diminished particle digestion are responsible for the decreased clearance of AC by diabetic Mfs. Fan et al (2006) linked deficient activation of small Rho GTPases, such as CdC42 and Rac, to altered cytoskeleton rearrangements in major murine models of spontaneous autoimmunity.…”

Section: Resultsmentioning

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: Introductionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

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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“…In these same experiments, it was also determined that clearance of the apoptotic cells (by macrophages, nonspecific cells of the innate immune system) is reduced in NOD mice, leading to the conjecture that material from these dead beta cells forms self-antigen that triggers the autoimmune response. Previous modelling efforts have focused on such early initiation events [12,13], but here we are mainly concerned with later stages in which the adaptive immune system is involved.…”

Section: Immunology Primermentioning

confidence: 99%

“…Equation (3.4) depicts our simple assumption about production and clearance of peptide: the level of "peptide," p, is produced with mass-action kinetics when effector cells kill beta cells (at rate R per effector per beta cell) and cleared with linear kinetics at rate δ p . Recall that clearance of dead beta-cells and their fragments by macrophages is defective in NOD mice [12,18,19], and this defect can theoretically lead to the early chronic inflammation that initiates the priming of T cells [13]. Therefore, it is of interest to ask whether this same defect can also account partly for the dynamics of T cells at this later stage of the disease.…”

Section: Model Equationsmentioning

confidence: 99%

Modeling Cyclic Waves of Circulating T Cells in Autoimmune Diabetes

Mahaffy¹,

Edelstein‐Keshet²

2007

SIAM J. Appl. Math.

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Abstract.Type 1 diabetes (T1D) is an autoimmune disease in which immune cells, notably T-lymphocytes target and kill the insulin-secreting pancreatic beta cells. Elevated blood sugar levels and full blown diabetes result once a large enough fraction of these beta cells have been destroyed. Recent investigation of T1D in animals, the non-obese diabetic (NOD) mice, has revealed large cyclic fluctuations in the levels of T cells circulating in the blood, weeks before the onset of diabetes [23], but the mechanism for these oscillations is unclear. We here describe a mathematical model for the immune response that suggests a possible explanation for the cyclic pattern of behaviour. We show that cycles similar to those observed experimentally can occur when activation of T cells is an increasing function of self-antigen level, whereas the production of memory cells declines with that level. Our model extends previous theoretical work on T cell dynamics in T1D [14], and leads to interesting nonlinear dynamics, including Hopf and homoclinic bifurcations in biologically reasonable regimes of parameters. The model leads to the following explanation for cycles: High rates of beta cell death, and corresponding elevation of self-antigen, shut off memory cell production, leading to a gap in the population of activated T cells. Once peptide has been cleared by nonspecific mechanisms, the memory pool is renewed, and the cyclic behaviour results.

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“…Mutations within the ELMO1 locus are associated with increased susceptibility to diabetic nephropathy (kidney disease associated with diabetes) (Shimazaki et al, 2005). Surprisingly, the NOD mouse, a popular diabetes model, has defects in phagocytosis of apoptotic cells, although this may be linked to other uncharacterized macrophage defects (Maree et al, 2005). Type I diabetes is in part due to autoimmune responses directed against the cells in the pancreas that produce insulin (Gillespie, 2006); whether this can be related to defects in engulfment of apoptotic cells, which also generates an autoimmune state, remains to be seen.…”

Section: Introductionmentioning

confidence: 99%

Journey to the grave: signaling events regulating removal of apoptotic cells

Kinchen

Ravichandran

2007

Journal of Cell Science

106

100

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Programmed cell death is critical both for organ formation during development and during adult life, when billions of cells must be removed every day. The culmination of the apoptotic process is the specific recognition and engulfment of the apoptotic cell by a phagocyte. A number of recent studies have revealed a series of evolutionarily conserved proteins that link corpse recognition to membrane movement, facilitating the internalization of the target and its subsequent degradation. Two potential signaling modules have been identified: one involving the CED-12/ELMO and CED-5/Dock180 proteins, which function as a bipartite guanine nucleotide exchange factor (GEF) for Rac1, and a second involving CED-1/LRP1 (a potential engulfment receptor) and the adaptor protein CED-6/GULP. Recognition of the apoptotic cell modulates cytokine secretion by the phagocyte, resulting in an anti-inflammatory state distinct from that induced by necrotic cells. The recent molecular delineation of the phagocytic process and the identification of novel signaling proteins involved in engulfment have provided an exciting new platform for future studies into this biologically important process.

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Quantifying macrophage defects in type 1 diabetes

Cited by 51 publications

References 20 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

Modeling Cyclic Waves of Circulating T Cells in Autoimmune Diabetes

Journey to the grave: signaling events regulating removal of apoptotic cells

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