TY - JOUR
T1 - Constitutive CD40 Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption
AU - Kusters, Pascal
AU - Seijkens, Tom
AU - Bürger, Christina
AU - Legein, Bart
AU - Winkels, Holger
AU - Gijbels, Marion
AU - Barthels, Christian
AU - Bennett, Remy
AU - Beckers, Linda
AU - Atzler, Dorothee
AU - Biessen, Erik
AU - Brocker, Thomas
AU - Weber, Christian
AU - Gerdes, Norbert
AU - Lutgens, Esther
N1 - Funding Information:
Supported by the Netherlands Organization for Scientific Research VICI grant (E.L.), the Netherlands CardioVascular Research Initiative grant CVON2011-19 (E.L.), Deutsche Forschungsgemeinschaft grants CRC1054-B04 (E.L.) and CRC1123-A5 (E.L., N.G., and C.W.), the European Research Council (E.L.), and the EU Horizon 2020 REPROGRAM grant (E.L.).
Publisher Copyright:
© 2017 American Society for Investigative Pathology
PY - 2017/12
Y1 - 2017/12
N2 - The costimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types, including mature dendritic cells (DCs), and is required for optimal T-cell activation and expansion. It remains undetermined whether and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here, the effects of constitutively active CD40 in DCs on atherosclerosis were examined using low-density lipoprotein-deficient (Ldlr−/−) bone marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40). As expected, DC-LMP1/CD40/Ldlr−/− chimeras (DC-LMP1/CD40) showed increased antigen-presenting capacity of DCs and increased T-cell numbers. However, the mice developed extensive neutrophilia compared to CD40wt/Ldlr−/− (CD40wt) chimeras. Despite overt T-cell expansion and neutrophilia, a reduction in conventional DC frequency and a dramatic (approximately 80%) reduction in atherosclerosis was observed. Further analyses revealed that cholesterol and triglyceride levels had decreased by 37% and 60%, respectively, in DC-LMP1/CD40 chimeras. Moreover, DC-LMP1/CD40 chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.
AB - The costimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types, including mature dendritic cells (DCs), and is required for optimal T-cell activation and expansion. It remains undetermined whether and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here, the effects of constitutively active CD40 in DCs on atherosclerosis were examined using low-density lipoprotein-deficient (Ldlr−/−) bone marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40). As expected, DC-LMP1/CD40/Ldlr−/− chimeras (DC-LMP1/CD40) showed increased antigen-presenting capacity of DCs and increased T-cell numbers. However, the mice developed extensive neutrophilia compared to CD40wt/Ldlr−/− (CD40wt) chimeras. Despite overt T-cell expansion and neutrophilia, a reduction in conventional DC frequency and a dramatic (approximately 80%) reduction in atherosclerosis was observed. Further analyses revealed that cholesterol and triglyceride levels had decreased by 37% and 60%, respectively, in DC-LMP1/CD40 chimeras. Moreover, DC-LMP1/CD40 chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.
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U2 - 10.1016/j.ajpath.2017.08.016
DO - 10.1016/j.ajpath.2017.08.016
M3 - Article
C2 - 28935569
AN - SCOPUS:85034269473
VL - 187
SP - 2912
EP - 2919
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 12
ER -