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CD40 Ligand Mediates Inflammation Independently of CD40 by Interaction With Mac-1

Zirlik, Andreas and Maier, Christoph and Gerdes, Norbert and MacFarlane, Lindsey and Soosairajah, Juliana and Bavendiek, Udo and Ahrens, Ingo and Ernst, Sandra and Bassler, Nicole and Missiou, Anna and Patko, Zsofia and Aikawa, Masanori and Schönbeck, Uwe and Bode, Christoph and Libby, Peter and Peter, Karlheinz (2007) CD40 Ligand Mediates Inflammation Independently of CD40 by Interaction With Mac-1. Circulation. pp. 1571-1580. ISSN 0009-7322 (print) 1524-4539 (online)

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Abstract

Background— Strong evidence supports a role for CD40 ligand (CD40L) as marker and mediator of inflammatory diseases such as atherosclerosis. Despite extensive characterization of CD40, the classic receptor of CD40L, its role in immune defense against inflammatory diseases remains uncertain. The present study aimed to characterize the contribution of CD40 signaling to atherogenesis. Methods and Results— Surprisingly, mice deficient in both CD40 and the low-density lipoprotein receptor did not develop smaller lesions in the aortic arch, root, and thoracoabdominal aorta compared with mice deficient only in the low-density lipoprotein receptor that consumed an atherogenic diet for 8 and 16 weeks. By flow cytometry, radioactive binding assays, and immunoprecipitation, we demonstrate that CD40L interacts with the integrin Mac-1, which results in Mac-1–dependent adhesion and migration of inflammatory cells as well as myeloperoxidase release in vitro. Furthermore, mice deficient in CD40L show significantly reduced thioglycolate-elicited invasion of inflammatory cells into the peritoneal cavity compared with mice deficient in CD40 and wild-type controls. Inhibition of Mac-1 in low-density lipoprotein receptor–deficient mice attenuates lesion development and reduces lesional macrophage accumulation. Conclusions— These observations identify the interaction of CD40L and Mac-1 as an alternative pathway for CD40L-mediated inflammation. This novel mechanism expands understanding of inflammatory signaling during atherogenesis.

Item Type: Article
Uncontrolled Keywords: atherosclerosis, cell adhesion molecules, leukocytes, CD40 ligand, mice
Subjects: FOR Classification > 0304 Medicinal and Bimolecular Chemistry
Faculty/School/Research Centre/Department > College of Health and Biomedicine
Depositing User: VUIR
Date Deposited: 04 Dec 2013 00:09
Last Modified: 04 Dec 2013 00:09
URI: http://vuir.vu.edu.au/id/eprint/22433
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Citations in Scopus: 78 - View on Scopus

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