Margaret A. Morris

National Institute of Allergy and Infectious Diseases

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Jerry L. Nadler

New York Medical College

Yumi Imai

Fraternal Order of Eagles

Raghavendra G. Mirmira

Indiana University – Purdue University Indianapolis

Julius O. Nyalwidhe

Eastern Virginia Medical School

Anca D. Dobrian

Eastern Virginia Medical School

Lindsey Glenn

Eastern Virginia Medical School

David Taylor

Eastern Health

Carla J. Greenbaum

Benaroya Research Institute

Peter Arvan

University of Michigan–Ann Arbor

Teresa L. Mastracci

Indiana University – Purdue University Indianapolis

Cooperative Institutions

University of Virginia

Eastern Virginia Medical School

Indiana University School of Medicine

Indiana University – Purdue University Indianapolis

Indiana University

The University of Texas Southwestern Medical Center

Indianapolis Zoo

Cairo University

Ain Shams University

Diabetes Australia

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12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Abhishek Kulkarni Annie R. Piñeros S. Jafar Ali Ibrahim Marimar Hernández‐Pérez Kara S. Orr

ABSTRACT Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The inflammatory signals and antigen presentation by these cells may be inducers of the adaptive immune response that is the hallmark of T1D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids from membrane-derived phospholipids, but its role and mechanisms in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of T1D-like islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β-cells and the subsequent development of hyperglycemia. Depletion or inhibition of 12-LOX in this model resulted in significantly reduced macrophage infiltration into islets with preservation of β-cell mass. In mice, we deleted the gene encoding 12-LOX ( Alox15 ) in the myeloid lineage in the non-obese diabetic (NOD) model of T1D. Myeloid cell-specific Alox15 knockout NOD mice demonstrated reduced insulitis and T-cell responses, preserved β cell mass, and almost complete protection from the development of T1D. A critical effect of 12-LOX depletion appeared secondary to a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration appeared to be secondary to the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migrator defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune myeloid cells in the early pathogenesis of T1D and identify 12-LOX as a necessary enzyme to promote their pro-diabetogenic phenotype in the context of autoimmunity.

Insulitis

NOD mice

10.1101/2021.01.02.424855

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Citations (2)

Relative sensitivity of immunohistochemistry, multiple reaction monitoring mass spectrometry, in situ hybridization and PCR to detect Coxsackievirus B1 in A549 cells

Journal of Clinical Virology (2016)

Jutta E. Laiho Maarit Oikarinen Sarah J. Richardson Gun Frisk Julius O. Nyalwidhe

Serial dilution

Coxsackievirus

clone (Java method)

10.1016/j.jcv.2016.01.015

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Citations (25)

Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Journal of the Endocrine Society (2017)

Julius O. Nyalwidhe Glen R. Gallagher Lindsey Glenn Margaret A. Morris Pranitha Vangala

Enteroviral infections have been associated with the development of type 1 diabetes (T1D), a chronic inflammatory disease characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Cultured human islets, including the insulin-producing beta cells, can be infected with coxsackievirus B4 (CVB4) and thus are useful for understanding cellular responses to infection. We performed quantitative mass spectrometry analysis on cultured primary human islets infected with CVB4 to identify molecules and pathways altered upon infection. Corresponding uninfected controls were included in the study for comparative protein expression analyses. Proteins were significantly and differentially regulated in human islets challenged with virus compared with their uninfected counterparts. Complementary analyses of gene transcripts in CVB4-infected primary islets over a time course validated the induction of RNA transcripts for many of the proteins that were increased in the proteomics studies. Notably, infection with CVB4 results in a considerable decrease in insulin. Genes/proteins modulated during CVB4 infection also include those involved in activation of immune responses, including type I interferon pathways linked to T1D pathogenesis and with antiviral, cell repair, and inflammatory properties. Our study applies proteomics analyses to cultured human islets challenged with virus and identifies target proteins that could be useful in T1D interventions.

Coxsackievirus

Pancreatic Islets

10.1210/js.2017-00278

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Citations (20)

Meeting report: Hidden links in autoimmunity

Science Immunology (2024)

Mireia Guerau‐de‐Arellano Margaret A. Morris Matthew A. Sherman Thomas R. Esch

A NIAID-sponsored workshop was held in September 2024, where challenges to understanding common mechanisms in autoimmune disease were discussed as opportunities to advance research.

10.1126/sciimmunol.ads5884

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Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance and vascular disease

Diabetes Obesity and Metabolism (2013)

Yumi Imai Anca D. Dobrian Jessica R. Weaver Martin Butcher Banumathi K. Cole

Abstract Inflammation is an established pathogenic player in insulin resistance, islet demise and atherosclerosis. The complex interactions between cytokines, immune cells and affected tissues result in sustained inflammation in diabetes and atherosclerosis. 12‐ and 15‐lipoxygenase ( LO ), such as 12/15‐ LO , produces a variety of metabolites through peroxidation of fatty acids and potentially contributes to the complex molecular crosstalk at the site of inflammation. 12‐ and 15‐ LO pathways are frequently activated in tissues affected by diabetes and atherosclerosis including adipose tissue ( AT ), islets and the vasculature. Moreover, mice with whole body and tissue‐specific knockout of 12/15‐ LO are protected against insulin resistance, hyperglycaemia and atherosclerosis supporting functional contribution of 12‐ and 15‐ LO pathways in diabetes and atherosclerosis. Recently, it has emerged that there is a temporal regulation of the particular isoforms of 12‐ and 15‐ LO in human AT and islets during the development of type 1 and type 2 diabetes and obesity. Analyses of tissues affected by diabetes and atherosclerosis also implied the roles of interleukin ( IL )‐12 and nicotinamide adenine dinucleotide phosphate ( NADPH ) oxidase‐1 ( NOX‐1 ) in islets and IL‐17A in atherosclerosis. Future studies should aim to test the efficacy of inhibitions of these mediators for treatment of diabetes and atherosclerosis.

10.1111/dom.12161

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Citations (80)

Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor

Circulation Research (2006)

Angela M. Whetzel David T. Bolick Suseela Srinivasan Timothy L. Macdonald Margaret A. Morris

Monocyte recruitment and adhesion to vascular endothelium are key early events in atherosclerosis. We examined the role of sphingosine-1-phosphate (S1P) on modulating monocyte/endothelial interactions in the NOD/LtJ (NOD) mouse model of type 1 diabetes. Aortas from nondiabetic and diabetic NOD mice were incubated in the absence or presence of 100 nmol/L S1P. Fluorescently labeled monocytes were incubated with the aortas. Aortas from NOD diabetic mice bound 7-fold more monocytes than nondiabetic littermates (10+/-1 monocytes bound/field for nondiabetic mice vs 74+/-12 monocytes bound/field for diabetic mice, P<0.0001). Incubation of diabetic aortas with 100 nmol/L S1P reduced monocyte adhesion to endothelium by 90%. We found expression of S1P1, S1P2, and S1P3 receptors on NOD aortic endothelial cells. The S1P1 receptor-specific agonist SEW2871 inhibited monocyte adhesion to diabetic aortas. Studies in diabetic S1P3-deficient mice revealed that the S1P3 receptor did not play a pivotal role in this process. S1P reduced endothelial VCAM-1 induction in type 1 diabetic NOD mice, most likely through inhibition of nuclear factor kappaB translocation to the nucleus. Thus, S1P activation of the S1P1 receptor functions in an antiinflammatory manner in type 1 diabetic vascular endothelium to prevent monocyte/endothelial interactions. S1P may play an important role in the prevention of vascular complications of type 1 diabetes.

Monocyte

Sphingosine-1-phosphate receptor

NOD mice

10.1161/01.res.0000244088.33375.52

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Citations (107)

ICAM-1 and LFA-1 play critical roles in LPS-induced neutrophil recruitment into the alveolar space

AJP Lung Cellular and Molecular Physiology (2006)

Abdul Basit Joerg Reutershan Margaret A. Morris Michael D. Solga Charles Rose

Neutrophil recruitment into lung constitutes a major response to airborne endotoxins. In many tissues endothelial intercellular adhesion molecule-1 (ICAM-1) interacts with lymphocyte function associated antigen-1 (LFA-1) on neutrophils, and this interaction plays a critical role in neutrophil recruitment. There are conflicting reports about the role of ICAM-1 in neutrophil recruitment into lungs. We studied neutrophil recruitment into alveolar space in a murine model of aerosolized LPS-induced lung inflammation. LPS induces at least a 100-fold increase in neutrophil numbers in alveolar space, as determined by flow cytometry of bronchoalveolar lavage fluid. Neutrophil recruitment was reduced by 54% in ICAM-1 null mice and by 45% in LFA-1 null mice. In wild-type mice treated with anti-ICAM-1 and anti-LFA-1 antibodies, there was 51 and 58% reduction in the neutrophil recruitment, respectively. In chimeric mice, generated by the transplantation of mixtures of bone marrows from LFA-1 null and wild-type mice, the normalized recruitment of LFA-1 null neutrophils was reduced by 60% compared with wild-type neutrophils. Neither the treatment of ICAM-1 null mice with a function-blocking antibody to LFA-1 nor the treatment of LFA-1 null mice with anti-ICAM-1 antibody resulted in further reduction in the recruitment compared with untreated ICAM-1 null and LFA-1 null mice. We conclude that ICAM-1 and LFA-1 play critical roles in the recruitment of neutrophils into the alveolar space in aerosolized LPS-induced lung inflammation, and LFA-1 serves as a ligand of ICAM-1 in the lung.

10.1152/ajplung.00346.2005

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Citations (130)

Response to Comment on Sims et al. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes. Diabetes Care 2019;42:258–264

Diabetes Care (2019)

Emily K. Sims Henry T. Bahnson Julius O. Nyalwidhe Leena Haataja Asa K. Davis

In a cohort of 319 individuals with long-duration type 1 diabetes (T1D), we found that 89.9% of participants with undetectable stimulated C-peptide had measurable fasting or stimulated serum proinsulin (1). To ensure the validity of our results, we performed rigorous validation of the Millipore human intact and Des (31,32) proinsulin radioimmunoassay that included spike-in experiments using insulin, C-peptide, and proinsulin; independent calculation of a lower limit of detection; assessment of inter- and intra-assay coefficients of variation; analysis of linearity of dilution; analysis of samples pre- and postpancreatectomy; analysis of effects of increased insulin autoantibody titers; and quantitative validation of our findings using mass spectrometry (1). The letter by Steenkamp et al. (2) in response to our article suggests the Millipore assay may overestimate proinsulin levels compared with the ALPCO STELLUX human total proinsulin ELISA. The authors’ concerns are based on their finding that, using the ALPCO assay, proinsulin was detected in only 16% of random samples from a smaller subset of C-peptide–negative individuals from the same T1D Exchange Residual C-peptide Study (3). Quantitative immunoassay performance differences between different assay platforms are not surprising due to antibody interactions with different epitopes on native antigens …

Proinsulin

Feature (linguistics)

10.2337/dci19-0012

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Citations (6)

Definition Of Additional Functional Ligands For Ly49IB6 Using FVBLy49IB6 Transgenic Mice And B6 Natural Killer Cell Effectors1

Transplantation (2002)

Margaret A. Morris Elena Koulich Jingxuan Liu Veera Arora Thaddeus C. George

Background. Natural killer (NK) cells use inhibitory Ly49 receptors to differentiate self from foreign cells based on interactions with major histocompatibility (MHC) class I molecules. Inhibitory receptors may recognize multiple MHC class I molecules. Studies to define ligands for the Ly49 receptors are complicated by the fact that receptors are expressed in overlapping subsets on NK cells. Binding studies can predict which MHC class I molecules are ligands for Ly49 receptors, but functional tests are required to substantiate results from binding studies. Methods. We developed Ly49 receptor transgenic mice and studied the function of Ly49IB6 in FVB.Ly49IB6 transgenic mice using bone marrow transplantation assays to determine additional functional ligands for Ly49IB6. We have also used fluorescence-activated cell sorting to isolate specific populations of B6 NK cells bearing Ly49I for use as effectors in 51chromium-release assays against a panel of Concanavalin A blast targets. Results. Bone marrow transplantation studies indicate that H2-Kb, H2s, and H2v serve as functional ligands for Ly49IB6. In vitro cytotoxicity assays indicate that Ly49I recognizes H2q, but not H2d or H2k, target cells to inhibit NK killing. Conclusions. These data add support to previous binding studies by showing functional interactions between the B6-strain Ly49I and H2-Kb, H2s, H2v, and H2q class I antigens.

10.1097/00007890-200211270-00018

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The Four-Way Stop Sign: Viruses, 12-Lipoxygenase, Islets, and Natural Killer Cells in Type 1 Diabetes Progression

Frontiers in Endocrinology (2017)

Michele L. Semeraro Lindsey Glenn Margaret A. Morris

Natural killer (NK) cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of type 1 diabetes (T1D) in at least a portion of patients. NK cells recognize their target cells through a delicate balance of inhibitory and stimulatory receptors on their surface. If unbalanced, NK cells have great potential to wreak havoc in the pancreas due to the beta cell expression of the as-yet-defined NKp46 ligand through interactions with the activating NKp46 receptor found on the surface of most NK cells. Blocking interactions between NKp46 and its ligand protects mice from STZ-induced diabetes, but differential expression non-diabetic and diabetic donor samples have not been tested. Additional studies have shown that peripheral blood NK cells from human T1D patients have altered phenotypes that reduce the lytic and functional ability of the NK cells. Investigations of humanT1D pancreas tissues have indicated that the presence of NK cells may be beneficial despite their infrequent detection. In non-obese diabetic (NOD) mice, we have noted that NK cells express high levels of the proinflammatory mediator 12/15-lipoxygenase (12/15-LO), and decreased levels of stimulatory receptors. Conversely, NK cells of 12/15-LO deficient NOD mice, which are protected from diabetes development, express significantly higher levels of stimulatory receptors. Furthermore, the human NK92 cell line expresses the ALOX12 protein [human 12-lipoxygenase (12-LO), related to mouse 12/15-LO] via Western blotting. Human 12-LO is upregulated in the pancreas of both T1D and T2D human donors with insulin-containing islets, showing a link between 12-LO expression and diabetes progression. Therefore, our hypothesis is that NK cells in those susceptible to developing T1D are unable to function properly during viral infections of pancreatic beta cells due to increased 12-LO expression and activation, which contributes to increased interferon-gamma production and an imbalance in activating and inhibitory NK cell receptors, and may contribute to downstream autoimmune T cell responses. The work presented here outlines evidence from our lab, as well as published literature, supporting our hypothesis, including novel data.

Lymphokine-activated killer cell

NOD mice

CD49b

Janus kinase 3

10.3389/fendo.2017.00246

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Citations (5)