Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes

Abstract

OBJECTIVE-12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic ␤-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of ␤-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in ␤-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse. RESEARCH DESIGN AND METHODS-We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15null ) using a "speed congenic" protocol, and the mice were monitored for development of insulitis and diabetes.RESULTS-NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. Ͼ60% in females by 30 weeks). Nondiabetic female NOD-Alox15 null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved ␤-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15 null mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4 ϩ T cells and increased Foxp3 ϩ cells.CONCLUSIONS-These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation.

Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2)

“…Collectively, these findings suggest that iPLA 2 ␤ deficiency mitigates polarization of macrophages toward an M1 phenotype. (42)(43)(44)(45). Consistent with this, we find that both ALOX-12 ( Fig.…”

“…12-S-hydroxyeicosatetraenoic acid) and is not detected in healthy islets but is in both T1D and T2D islets (42), is induced to a much higher level in WT macrophages than in iPLA 2 ␤-deficient macrophages. The importance of 12-LO in promoting macrophage recruitment and activation and causing detrimental effects on islet function and ␤-cell mass is supported by the reports that deletion of 12-LO protects against T1D development (44,45). Our findings, therefore, suggest that iPLA 2 ␤ activation, in addition to skewing macrophage polarization toward M1, may also preserve functionality of downstream lipidmetabolizing enzymes.…”

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

“…Deletion of 12-lipoxygenase protects mice against hyperglycaemia induced with low dose streptozotocin. In the NOD mouse, 12-lipoxygenase deletion confers a near complete protection against type 1 diabetes and also reduces immune cell activation [17,23]. Interestingly, two independent groups have shown that 12-lipoxygenase activation also participates in high-fat-induced insulin resistance and adipose tissue inflammation [24,25].…”

“…Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22]. Recent evidence indicates that increased expression of 12-lipoxygenase in islets is a common feature of both rodent and human models of type 1 and type 2 diabetes [11,13,15,17,22]. Deletion of 12-lipoxygenase protects mice against hyperglycaemia induced with low dose streptozotocin.…”

“…12-Lipoxygenase is an oxygenase for arachidonic acid (AA) and other fatty acids, leading to proinflammatory lipids including 12-S-hydroperoxieicosatetraenoic acid (12-S-HPETE) and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE) [14,15]. 12-Lipoxygenase is expressed in rodent and human islets [11,[15][16][17][18] and is upregulated under conditions of metabolic and cytokine stress. Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22].…”