OBJECTIVE: Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. METHODS: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-. RESULTS: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.
OBJECTIVE: Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. METHODS: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-. RESULTS: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atheroscleroticmice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.
Authors: Jargalsaikhan Dagvadorj; Karolina Mikulska-Ruminska; Gantsetseg Tumurkhuu; Rojo A Ratsimandresy; Jessica Carriere; Allen M Andres; Stefanie Marek-Iannucci; Yang Song; Shuang Chen; Malcolm Lane; Andrea Dorfleutner; Roberta A Gottlieb; Christian Stehlik; Suzanne Cassel; Fayyaz S Sutterwala; Ivet Bahar; Timothy R Crother; Moshe Arditi Journal: Proc Natl Acad Sci U S A Date: 2021-01-05 Impact factor: 11.205
Authors: Seth G Thacker; Abdalrahman Zarzour; Ye Chen; Mustafa S Alcicek; Lita A Freeman; Dennis O Sviridov; Stephen J Demosky; Alan T Remaley Journal: Immunology Date: 2016-08-28 Impact factor: 7.397