Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis.
Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineage-specific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1beta expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2(-/-) ApoE(-/-) cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis.
Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne, D-50931 Cologne, Germany.
Julia
J
Baumgartl
Stephanie
S
Baudler
Maximilian
M
Scherner
Vladimir
V
Babaev
Liza
L
Makowski
Jill
J
Suttles
Marcia
M
McDuffie
Kazuyuki
K
Tobe
Takashi
T
Kadowaki
Sergio
S
Fazio
C Ronald
CR
Kahn
Gökhan S
GS
Hotamisligil
Wilhelm
W
Krone
Macrae
M
Linton
Jens C
JC
Brüning
D019264:Adoptive Transfer; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015153:Blotting, Western; D002460:Cell Line; D019070:Cell Lineage; D047468:Immunoprecipitation; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
D001057:Apolipoproteins E; D007328:Insulin; D007375:Interleukin-1; D015850:Interleukin-6; D011972:Receptor, Insulin