Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development

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

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23 Scopus citations

Abstract

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-Alox15null 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-Alox15null 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.

Original languageEnglish (US)
Article numbere56763
JournalPLoS ONE
Volume8
Issue number2
DOIs
StatePublished - Feb 21 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Green-Mitchell, S. M., Tersey, S. A., Cole, B. K., Ma, K., Kuhn, N. S., Cunningham, T. D., Maybee, N. A., Chakrabarti, S. K., McDuffie, M., Taylor-Fishwick, D. A., Mirmira, R. G., Nadler, J. L., & Morris, M. A. (2013). Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development. PLoS ONE, 8(2), [e56763]. https://doi.org/10.1371/journal.pone.0056763