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(Circulation. 2007;115:1571-1580.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

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

Andreas Zirlik, MD^*; Christoph Maier, MS^*; Norbert Gerdes, PhD; Lindsey MacFarlane, BS; Juliana Soosairajah, PhD; Udo Bavendiek, MD; Ingo Ahrens, MD; Sandra Ernst, BS; Nicole Bassler, BS; Anna Missiou, MD; Zsofia Patko, MD; Masanori Aikawa, MD, PhD; Uwe Schönbeck, MD; Christoph Bode, MD; Peter Libby, MD; Karlheinz Peter, MD

From the Donald W. Reynolds Center (A.Z., N.G., L.M., M.A., U.S., P.L.), Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Mass; Department of Cardiology (A.Z., C.M., I.A., S.E., A.M., Z.P., C.B.), University of Freiburg, Freiburg, Germany; Department of Cardiology (U.B.), University of Hannover, Hannover, Germany; Cardiovascular Research (U.S.), Boehringer Ingelheim, Ridgefield, Conn; and Centre for Atherothrombosis & Myocardial Infarction (J.S., N.B., K.P.), Baker Heart Research Institute, Melbourne, Australia.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB-741, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Received August 22, 2006; accepted January 9, 2007.

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.

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