Pancreatic islet inflammation is a shared characteristic of type 1 and type 2 diabetes pathogenesis, and macrophage infiltration has been shown to exacerbate this inflammation. The enzyme 12/15-Lipoxygenase (12/15-LOX) which is involved in polyunsaturated fatty acid metabolism, has also been implicated in islet inflammation. Based on its established roles in cellular migration in other contexts, we hypothesized that 12/15-LOX promotes macrophage infiltration. To test this hypothesis, we used two complementary model systems: zebrafish and mice. First, we knocked down 12/15-LOX in Tg(ins:NTR) zebrafish with an antisense morpholino. When these zebrafish are treated with the prodrug metronidazole (MTZ), β cells are specifically injured, and macrophages accumulate in the islet. After a 6-hour incubation with MTZ, we observed a significant reduction in the number of infiltrating macrophages in the islets of 12/15-LOX knockdown larvae as compared to control larvae (2.7±0.8 vs. 1.17±0.7, P<0.05). Similarly, injured β cells in zebrafish treated with the 12/15-LOX inhibitor ML355 showed a significant reduction in the number of islet-infiltrating macrophages compared to vehicle-treated larvae (3.67±0.7 vs. 1.2±0.3, P<0.05). Next, using transwell assays, we measured the migration of peritoneal macrophages that were isolated from 12/15-LOX knockout mice in media that was conditioned by islet culture. Again, we observed a significant reduction in macrophage migration with 12/15-LOX deficiency compared to controls (162.8±15.5 vs. 108.4±15.1, P<0.05). Mechanistically, we found that the expression of the chemokine receptor CXCR3 was significantly downregulated in 12/15-LOX-knockout macrophages. Taken together, our data reveal a role for 12/15-LOX in macrophage migration that is conserved across species. Importantly, our study indicates that the signaling pathways downstream from 12/15-LOX are potential therapeutic targets for the resolution of inflammation-induced damage in the islets.


A. Kulkarni: None. A. Pineros: None. S. Ibrahim: None. M. Hernandez-Perez: None. S.A. Tersey: None. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. R.M. Anderson: None.

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