Nonobese diabetic (NOD) mice congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes.
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 beta-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of beta-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in beta-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.


METHODS
We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15(null)) 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. >60% 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 beta-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(+) T cells and increased Foxp3(+) 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.
McDuffie
Marcia
M
University of Virginia, P.O. Box 801405, Charlottesville, VA 22908, USA.
Maybee
Nelly A
NA
Keller
Susanna R
SR
Stevens
Brian K
BK
Garmey
James C
JC
Morris
Margaret A
MA
Kropf
Elizabeth
E
Rival
Claudia
C
Ma
Kaiwen
K
Carter
Jeffrey D
JD
Tersey
Sarah A
SA
Nunemaker
Craig S
CS
Nadler
Jerry L
JL
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics*; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D016678:Genome; D006029:Glycosuria / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008262:Macrophage Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D017384:Sequence Deletion; D013623:Tail
C475064:12-15-lipoxygenase; D017931:DNA Primers; D004247:DNA; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase