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, Raghu Mirmira, Jerry L. Nadler, Margaret A. Morris

Research output: Contribution to journalArticle

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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
Article numbere56763
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 21 2013

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Inbred NOD Mouse
insulin-dependent diabetes mellitus
Macrophages
Medical problems
lipoxygenase
Type 1 Diabetes Mellitus
macrophages
cytokines
Cytokines
mice
Adoptive Transfer
splenocytes
Polymerase Chain Reaction
diabetes
Transcription Factors
transcription factors
Health
cells
autoimmunity
T-cells

ASJC Scopus subject areas

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

Cite this

Green-Mitchell, S. M., Tersey, S. A., Cole, B. K., Ma, K., Kuhn, N. S., Cunningham, T. D., ... 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

Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development. / 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, Raghu; Nadler, Jerry L.; Morris, Margaret A.

In: PLoS One, Vol. 8, No. 2, e56763, 21.02.2013.

Research output: Contribution to journalArticle

Green-Mitchell, SM, Tersey, SA, Cole, BK, Ma, K, Kuhn, NS, Cunningham, TD, Maybee, NA, Chakrabarti, SK, McDuffie, M, Taylor-Fishwick, DA, Mirmira, R, Nadler, JL & Morris, MA 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, vol. 8, no. 2, e56763. https://doi.org/10.1371/journal.pone.0056763
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, Raghu ; Nadler, Jerry L. ; Morris, Margaret A. / Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development. In: PLoS One. 2013 ; Vol. 8, No. 2.
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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.",
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AU - Tersey, Sarah A.

AU - Cole, Banumathi K.

AU - Ma, Kaiwen

AU - Kuhn, Norine S.

AU - Cunningham, Tina Duong

AU - Maybee, Nelly A.

AU - Chakrabarti, Swarup K.

AU - McDuffie, Marcia

AU - Taylor-Fishwick, David A.

AU - Mirmira, Raghu

AU - Nadler, Jerry L.

AU - Morris, Margaret A.

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Y1 - 2013/2/21

N2 - 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.

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