IU Indianapolis ScholarWorks :: Browsing by Author "Nadler, Jerry L."

Browsing by Author "Nadler, Jerry L."

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12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes
(The American Society for Clinical Investigation, 2021-07-22) Kulkarni, Abhishek; Pineros, Annie R.; Walsh, Melissa A.; Casimiro, Isabel; Ibrahim, Sara; Hernandez-Perez, Marimar; Orr, Kara S.; Glenn, Lindsey; Nadler, Jerry L.; Morris, Margaret A.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of Medicine
Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.
12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets
(Oxford University Press, 2017-08-01) Ma, Kaiwen; Xiao, An; Park, So Hyun; Glenn, Lindsey; Jackson, Laura; Barot, Tatvam; Weaver, Jessica R.; Taylor-Fishwick, David A.; Luci, Diane K.; Maloney, David J.; Mirmira, Raghavendra G.; Imai, Yumi; Nadler, Jerry L.; Pediatrics, School of Medicine
Context: The 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D). Objectives: We aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function. Design: Human islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355. Setting: In vitro study. Participants: Human islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%. Intervention: Glucose stimulation. Main Outcome Measures: Static and dynamic insulin secretion and oxygen consumption rate (OCR). Results: ML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors. Conclusions: ML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo.
12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets
(American Society for Microbiology (ASM), 2014-10) Tersey, Sarah A.; Maier, Bernhard; Nishiki, Yurika; Maganti, Aarthi V.; Nadler, Jerry L.; Mirmira, Raghavendra G.; Department of Pediatrics, IU School of Medicine
High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.
Amelioration of type 1 diabetes following treatment of non-obese diabetic mice with INGAP and lisofylline
(SciRes, 2012-05-01) Tersey, Sarah A.; Carter, Jeffery D.; Rosenberg, Lawrence; Taylor-Fishwick, David A.; Mirmira, Raghavendra G.; Nadler, Jerry L.; Department of Pediatrics, School of Medicine
Type 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.
Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
(American Diabetes Association, 2017-11) Hernandez-Perez, Marimar; Chopra, Gaurav; Fine, Jonathan; Conteh, Abass M.; Anderson, Ryan M.; Linnemann, Amelia K.; Benjamin, Chanelle; Nelson, Jennifer B.; Benninger, Kara S.; Nadler, Jerry L.; Maloney, David J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation
(Hindawi Publishing Corporation, 2017) Dobrian, Anca D.; Ma, Kaiwen; Glenn, Lindsey M.; Hatcher, Margaret A.; Haynes, Bronson A.; Lehrer, Eric J.; Kaplan, Mark H.; Nadler, Jerry L.; Pediatrics, School of Medicine
Dobrian, A. D., Ma, K., Glenn, L. M., Hatcher, M. A., Haynes, B. A., Lehrer, E. J., … Nadler, J. L. (2017). Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation. Mediators of Inflammation, 2017, 5420718. http://doi.org/10.1155/2017/5420718
Minireview: 12-Lipoxygenase and Islet β-Cell Dysfunction in Diabetes
(The Endocrine Society, 2015-06) Tersey, Sarah A.; Bolanis, Esther; Holman, Theodore R.; Maloney, David J.; Nadler, Jerry L.; Mirmira, Raghavendra G.; Department of Pediatrics, IU School of Medicine
The insulin producing islet β-cells have increasingly gained attention for their role in the pathogeneses of virtually all forms of diabetes. Dysfunction, de-differentiation, and/or death of β-cells are pivotal features in the transition from normoglycemia to hyperglycemia in both animal models of metabolic disease and humans. In both type 1 and type 2 diabetes, inflammation appears to be a central cause of β-cell derangements, and molecular pathways that modulate inflammation or the inflammatory response are felt to be prime targets of future diabetes therapy. The lipoxygenases (LOs) represent a class of enzymes that oxygenate cellular polyunsaturated fatty acids to produce inflammatory lipid intermediates that directly and indirectly affect cellular function and survival. The enzyme 12-LO is expressed in all metabolically active tissues, including pancreatic islets, and has received increasing attention for its role in promoting cellular inflammation in the setting of diabetes. Genetic deletion models of 12-LO in mice reveal striking protection from metabolic disease and its complications and an emerging body of literature has implicated its role in human disease. This review focuses on the evidence supporting the proinflammatory role of 12-LO as it relates to islet β-cells, and the potential for 12-LO inhibition as a future avenue for the prevention and treatment of metabolic disease.
Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes
(Elsevier, 2022) Piñeros, Annie R.; Kulkarni, Abhishek; Gao, Hongyu; Orr, Kara S.; Glenn, Lindsey; Huang, Fei; Liu, Yunlong; Gannon, Maureen; Syed, Farooq; Wu, Wenting; Anderson, Cara M.; Evans-Molina, Carmella; McDuffie, Marcia; Nadler, Jerry L.; Morris, Margaret A.; Mirmira, Raghavendra G.; Tersey, Sarah A.; Pediatrics, School of Medicine
Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.
STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation
(American Diabetes Association, 2013-12) Dobrian, Anca D.; Galkina, Elena V.; Ma, Qian; Hatcher, Margaret; Aye, Sabai Myo; Butcher, Mathew J.; Ma, Kaiwen; Haynes, Bronson A.; Kaplan, Mark H.; Nadler, Jerry L.; Department of Pediatrics, IU School of Medicine
Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4(-/-)C57Bl6/J mice develop high-fat diet-induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4(-/-) mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8(+) cells, and display increased alternative (M2) macrophage polarization. CD8(+) cells, but not CD4(+) cells, from STAT4(-/-) mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4(-/-) mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity.
STAT4 deficiency reduces the development of atherosclerosis in mice
(Elsevier, 2015-11) Taghavie-Moghadam, Parésa L.; Gjurich, Breanne N.; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H.; Dobrian, Anca D.; Nadler, Jerry L.; Galkina, Elena V.; Department of Pediatrics, IU School of Medicine
Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses.

Browsing by Author "Nadler, Jerry L."

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