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

Abstract

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.

Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

“…Although adaptive immune cells do not express detectable levels of 12/15-LOX, natural killer (NK) cells express surprisingly high levels of 12/15-LOX (Semeraro et al, 2017). NK cells from congenic Alox15-deficient NOD mice display significantly higher levels of stimulatory receptors on their surface as compared to wild-type NOD NK cells , a finding that correlates with results seen in non-diabetic human NK cells as compared to those from donors with T1D (Qin et al, 2011).…”

Mutagenesis, Hydrogen–Deuterium Exchange, and Molecular Docking Investigations Establish the Dimeric Interface of Human Platelet-Type 12-Lipoxygenase

“…Human platelet 12 S -lipoxygenase (h12-LOX or ALOX12) adds molecular oxygen at C-12 of arachidonic acid (AA) with S chirality to generate 12­( S )-hydroperoxyeicosatetraenoic acid [12 S -HpETE]. − This hydroperoxide is subsequently reduced by glutathione peroxidase to yield 12­( S )-hydroxyeicosatetraenoic acid [12 S -HETE]. − These h12-LOX products, as well as others from different fatty acids, influence platelet aggregation and play a role in many inflammatory diseases, such as psoriasis, diabetes, − and cancer, − indicating h12-LOX as a possible therapeutic target. ,, Currently, the main effort in the search for inhibitors targeting lipoxygenases has been directed to the active site, blocking the direct enzymatic activity of fatty acid peroxidation. However, allosteric inhibition may also be relevant, as seen for cyclooxygenase (COX). , …”

Dietary Fish Oil Increases the Number of CD11b+CD27− NK Cells at the Inflammatory Site and Enhances Key Hallmarks of Resolution of Murine Antigen-Induced Peritonitis

“… 51 , 52 The lower concentrations of the AA-derived PGs, TBx 2 and HETEs could also contribute to a less pro-inflammatory environment in the fish oil fed mice to ensure proper resolution of the antigen-induced peritonitis. 53 NK cells have been shown to express high levels of 12/15-LOX in a murine model of type I diabetes 22 and could, therefore, be the source of the 12- and 15-HEPEs in the present study. Very low concentrations of the SPMs, maresin 1, protectin D 1 , protectin D x , and resolvin D 2 were detected based on retention time matching and a characteristic mass transition in peritoneal lavage of mice fed both diets (data not shown).…”

“… 19–21 Interestingly, NK cells have recently been shown to express high levels of 12/15-LOX, the murine ortholog of human 15-LOX, in a murine model of type I diabetes. 22 However, it remains unclear whether NK cells exert pro-resolution functions through the production of SPMs or their precursors.…”