CD70-driven chronic immune activation is protective against atherosclerosis.
Chronic infection and inflammation are strongly associated with the development of atherosclerosis. To investigate whether chronic inflammation in the absence of an infectious cause also predisposes to the development of atherosclerosis, we used a mouse model in which sterile inflammation is driven by enhanced costimulation. Constitutive triggering of CD27 on T cells through overexpression of CD70 on B cells increases the numbers of IFN gamma-producing effector T cells, which reduces the numbers of B cells. However, despite these pro-atherogenic features, we found that CD70-transgenic (CD70TG) mice on an ApoE*3-Leiden background were strongly protected against the induction of atherosclerotic lesions, with a normal increase in serum cholesterol level and the absence of atheroprotective antibodies. We found that circulating monocytes in CD70TG mice were activated and increased in numbers, in particular the pool of inflammatory (Ly6C(+)) monocytes. Importantly, monocytes from CD70TG mice had no defects in phagocytosis nor in TNFalpha production, but they were more prone to apoptosis, which was IFN gamma-dependent. These data indicate that sterile pro-inflammatory conditions can be protective against atherosclerosis development, possibly due to a reduced viability of circulating monocytes. This unexpected outcome provides a new insight into the consequences of costimulatory signals and their impact on innate immunity.
van Olffen
Ronald W
RW
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
de Bruin
Alex M
AM
Vos
Mariska
M
Staniszewska
Anna D
AD
Hamann
Jörg
J
van Lier
René A W
RA
de Vries
Carlie J M
CJ
Nolte
Martijn A
MA
D000818:Animals; D001057:Apolipoproteins E / Q000276:immunology; D017209:Apoptosis; D050197:Atherosclerosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D053282:CD27 Ligand / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D010587:Phagocytosis; D013601:T-Lymphocytes / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000276:immunology
D001057:Apolipoproteins E; D053282:CD27 Ligand; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7