Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15(null) Mice, Leading to Protection against Type 1 Diabetes Development

作者：Green Mitchell Shamina M; Tersey Sarah A; Cole Banumathi K; Ma Kaiwen; Kuhn Norine S; Cunningham Tina Duong; Maybee Nelly A; Chakrabarti Swarup K; McDuffie Marcia; Taylor Fishwick David A; Mirmira Raghavendra G; Nadler Jerry L; Morris Margaret A^*

来源：PLos One, 2013, 8(2): e56763.

DOI：10.1371/journal.pone.0056763

Aims: Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D.
Methods: 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass.
Results: 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass.
Conclusions: These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.

• 出版日期2013-2-21