Browsing by Author "Singer, Kanakadurga"

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    CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity
    (Society for Leukocyte Biology, 2016-06) Morris, David L.; Oatmen, Kelsie E.; Mergian, Taleen A.; Cho, Kae Won; DelProposto, Jennifer L.; Singer, Kanakadurga; Evans-Molina, Carmella; O’Rourke, Robert W.; Lumeng, Carey N.; Medicine, School of Medicine
    Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
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    Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells
    (Elsevier, 2014-07-10) Singer, Kanakadurga; DelProposto, Jennifer; Morris, David Lee; Zamarron, Brian; Mergian, Taleen; Maley, Nidhi; Cho, Kae Won; Geletka, Lynn; Subbaiah, Perla; Muir, Lindsey; Martinez-Santibanez, Gabriel; Lumeng, Carey Nien-Kai; Medicine, School of Medicine
    Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c(+) adipose tissue macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c(+) adipose tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to adipose tissue inflammation.
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    Doris Duke Charitable Foundation Fund to Retain Clinical Scientists: innovating support for early-career family caregivers
    (American Society for Clinical Investigation, 2022-12-01) Jagsi, Reshma; Beeland, T. DeLene; Sia, Kevin; Szczygiel, Lauren A.; Allen, Matthew R.; Arora, Vineet M.; Bair-Merritt, Megan; Bauman, Melissa D.; Bogner, Hillary R.; Daumit, Gail; Davis, Esa; Fagerlin, Angela; Ford, Daniel E.; Gbadegesin, Rasheed; Griendling, Kathy; Hartmann, Katherine; Hedayati, S. Susan; Jackson, Rebecca D.; Matulevicius, Susan; Mugavero, Michael J.; Nehl, Eric J.; Neogi, Tuhina; Regensteiner, Judith G.; Rubin, Michael A.; Rubio, Doris; Singer, Kanakadurga; Tucker Edmonds, Brownsyne; Volerman, Anna; Laney, Sandra; Patton, Carrie; Escobar Alvarez, Sindy; Anatomy, Cell Biology and Physiology, School of Medicine
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    Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice
    (American Association of Immunologists, 2021) Nandedkar-Kulkarni, Neha; Esakov, Emily; Gregg, Brigid; Atkinson, Mark A.; Rogers, Douglas G.; Horner, James D.; Singer, Kanakadurga; Lundy, Steven K.; Felton, Jamie L.; Al-Huniti, Tasneem; Kalinoski, Andrea Nestor; Morran, Michael P.; Gupta, Nirdesh K.; Bretz, James D.; Balaji, Swapnaa; Chen, Tian; McInerney, Marcia F.; Pediatrics, School of Medicine
    Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.
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    Sustaining the Pediatric Endocrinology Workforce: Recommendations from the Pediatric Endocrine Society Workforce Task Force
    (Elsevier, 2021-06) Allen, David B.; Aye, Tandy; Boney, Charlotte M.; Eugster, Erica A.; Misra, Madhusmita; Singer, Kanakadurga; Stafford, Diane; Witchel, Selma F.; Zeitler, Philip; Pediatrics, School of Medicine