on June 3, 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134378.86443.cd
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Submitted on March 2, 2004
Accepted on April 29, 2004
Leukocyte-Derived Interleukin 10 Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
Stéphane Potteaux ;
From the Institut National de la Santé et de la Recherche Médicale, (INSERM) U541 (S.P., B.E., O.V.O., A.T., Z.M.), Institut Fédératif de Recherche "Circulation Paris VII," Hôpital Lariboisière, Paris, France; TxCell, Bat. ARC (V.B.) and INSERM U576 (V.B., H.G.), Hôpital de l’Archet, Nice, France; and Institut Gustave Roussy (P.A.), Villejuif, France.
* To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.
Background--Atherosclerosis is an immunoinflammatory disease. Here we examined the role of leukocyte-derived interleukin 10 (IL-10) on advanced atherosclerosis development in low-density lipoprotein receptor knockout (LDLr-/-) mice.
Methods and Results--Bone marrow cells harvested from C57BL/6 IL-10-/- and IL-10+/+ mice were transplanted into irradiated male LDLr-/- mice. Four weeks after transplantation, mice were fed a high-fat cholate-free diet for 14 weeks. Despite no differences in weights, serum total, and HDL-cholesterol levels between the 2 groups, IL-10 deficiency in leukocytes induced a >2-fold increase in lesion development in the thoracic aorta compared with controls. We also found a significant 35% increase in aortic root lesion area of IL-10-/- mice compared with IL-10+/+ mice. Furthermore, IL-10 deficiency led to a marked increase in lymphocyte and macrophage accumulation associated with a significant reduction in collagen accumulation. Finally, transfer of IL-10-/- splenocytes to LDLr-/- mice resulted in a 3-fold increase in lesion size in the aortic sinus compared with mice transplanted with IL-10+/+ splenocytes.
Conclusion--IL-10 expressed by leukocytes prevents exaggerated advanced atherosclerosis development and plays a critical role in modulation of cellular and collagen plaque composition, at least in part, through a modulation of the systemic immune response.
Key words: atherosclerosis • leukocytes • inflammation
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