Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134378.86443.cd
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Leukocyte-Derived Interleukin 10 Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
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.
Correspondence to Ziad Mallat, MD, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France. 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.
Here we show that IL-10 deficiency in leukocytes induced 2-fold increase in lesion development in the thoracic aorta of LDLr –/– mice compared with controls. Furthermore, IL-10 deficiency led to a marked increase in the accumulation of both lymphocytes and macrophages, 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 in comparison with mice transplanted with IL-10+/+ splenocytes.
Key Words: atherosclerosis • leukocytes • inflammation
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