12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes

ABSTRACTMacrophages 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.

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Faculty Opinions recommendation of TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1058722.517805 ◽

2007 ◽

Author(s):

Steve Rattigan

Keyword(s):

Beta Cell ◽

Sensory Neurons ◽

Autoimmune Diabetes ◽

Cell Stress ◽

Islet Inflammation

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Faculty Opinions recommendation of TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1058722.510633 ◽

2006 ◽

Author(s):

George Eisenbarth

Keyword(s):

Beta Cell ◽

Sensory Neurons ◽

Autoimmune Diabetes ◽

Cell Stress ◽

Islet Inflammation

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Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽

10.1152/physiol.00032.2009 ◽

2009 ◽

Vol 24 (6) ◽

pp. 325-331 ◽

Cited By ~ 171

Author(s):

Marc Y. Donath ◽

Marianne Böni-Schnetzler ◽

Helga Ellingsgaard ◽

Jan A. Ehses

Keyword(s):

Type 2 Diabetes ◽

Cell Mass ◽

Metabolic Stress ◽

Innate Immune ◽

Pancreatic Β Cell ◽

Β Cell ◽

Amyloid Deposits ◽

Impaired Insulin ◽

Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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Contribution of the Innate Immune System to Autoimmune Diabetes: A Role for the CR1/CR2 Complement Receptors

Cellular Immunology ◽

10.1006/cimm.1999.1522 ◽

1999 ◽

Vol 195 (1) ◽

pp. 75-79 ◽

Cited By ~ 31

Author(s):

Hooman Noorchashm ◽

Daniel J. Moore ◽

Yen K. Lieu ◽

Negin Noorchashm ◽

Alexander Schlachterman ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Autoimmune Diabetes ◽

Innate Immune ◽

Complement Receptors

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Faculty Opinions recommendation of TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1058722.510692 ◽

2006 ◽

Author(s):

Mark Atkinson

Keyword(s):

Beta Cell ◽

Sensory Neurons ◽

Autoimmune Diabetes ◽

Cell Stress ◽

Islet Inflammation

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Two Genetic Loci Regulate T Cell–Dependent Islet Inflammation and Drive Autoimmune Diabetes Pathogenesis

The American Journal of Human Genetics ◽

10.1086/302995 ◽

2000 ◽

Vol 67 (1) ◽

pp. 67-81 ◽

Cited By ~ 42

Author(s):

Casey J. Fox ◽

Andrew D. Paterson ◽

Steven M. Mortin-Toth ◽

Jayne S. Danska

Keyword(s):

T Cell ◽

Autoimmune Diabetes ◽

Genetic Loci ◽

Islet Inflammation

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Lessons on autoimmune diabetes from animal models

Clinical Science ◽

10.1042/cs20050330 ◽

2006 ◽

Vol 110 (6) ◽

pp. 627-639 ◽

Cited By ~ 61

Author(s):

Yang Yang ◽

Pere Santamaria

Keyword(s):

Animal Models ◽

Autoimmune Diabetes ◽

Type I Diabetes ◽

Vascular Complications ◽

Diabetic Mouse ◽

Suboptimal Control ◽

Type I ◽

Genetic Elements ◽

Glucose Levels ◽

Islet Inflammation

T1DM (Type I diabetes mellitus) results from selective destruction of the insulin-producing β-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of T1DM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that T1DM is caused by autoreactive T-lymphocytes and revealed that the development of T1DM is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of T1DM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of T1DM. In this review, we summarize the contribution of studies in animal models of T1DM to our current understanding of four fundamental aspects of T1DM: (i) the nature of genetic elements affording T1DM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and β-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.

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Heme Oxygenase-1 Induction Prevents Autoimmune Diabetes in Association With Pancreatic Recruitment of M2-Like Macrophages, Mesenchymal Cells, and Fibrocytes

Endocrinology ◽

10.1210/en.2015-1304 ◽

2015 ◽

Vol 156 (11) ◽

pp. 3937-3949 ◽

Cited By ~ 11

Author(s):

Mahmoud Husseini ◽

Gen-Sheng Wang ◽

Christopher Patrick ◽

Jennifer A. Crookshank ◽

Amanda J. MacFarlane ◽

...

Keyword(s):

Heme Oxygenase ◽

Autoimmune Diabetes ◽

Interstitial Cells ◽

Mesenchymal Cells ◽

Heme Oxygenase 1 ◽

M2 Macrophage ◽

Rt Pcr ◽

Short Term ◽

Islet Inflammation

Immunoregulatory and regenerative processes are activated in the pancreas during the development of type 1 diabetes (T1D) but are insufficient to prevent the disease. We hypothesized that the induction of cytoprotective heme oxygenase-1 (HO-1) by cobalt protophoryrin (CoPP) would prevent T1D by promoting anti-inflammatory and pro-repair processes. Diabetes-prone BioBreeding rats received ip CoPP or saline twice per week for 3 weeks, starting at 30 days and were monitored for T1D. Immunohistochemistry, confocal microscopy, quantitative RT-PCR, and microarrays were used to evaluate postinjection pancreatic changes at 51 days, when islet inflammation is first visible. T1D was prevented in CoPP-treated rats (29% vs 73%). Pancreatic Hmox1 was up-regulated along with islet-associated CD68+HO-1+cells, which were also observed in a striking peri-lobular interstitial infiltrate. Most interstitial cells expressed the mesenchymal marker vimentin and the hematopoietic marker CD34. Spindle-shaped, CD34+vimentin+ cells coexpressed collagen V, characteristic of fibrocytes. M2 macrophage factors Krüppel-like factor 4, CD163, and CD206 were expressed by interstitial cells, consistent with pancreatic upregulation of several M2-associated genes. CoPP upregulated islet-regenerating REG genes and increased neogenic REG3β+ and insulin+ clusters. Thus, short-term induction of HO-1 promoted a protective M2-like milieu in the pancreas and recruited mesenchymal cells, M2 macrophages, and fibrocytes that imparted immunoregulatory and pro-repair effects, preventing T1D.

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