title: CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1.
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.
  
  
  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.
authors: Donald W. Reynolds Center, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Andreas
authors: A
authors: Zirlik
authors: Christoph
authors: C
authors: Maier
authors: Norbert
authors: N
authors: Gerdes
authors: Lindsey
authors: L
authors: MacFarlane
authors: Juliana
authors: J
authors: Soosairajah
authors: Udo
authors: U
authors: Bavendiek
authors: Ingo
authors: I
authors: Ahrens
authors: Sandra
authors: S
authors: Ernst
authors: Nicole
authors: N
authors: Bassler
authors: Anna
authors: A
authors: Missiou
authors: Zsofia
authors: Z
authors: Patko
authors: Masanori
authors: M
authors: Aikawa
authors: Uwe
authors: U
authors: Schönbeck
authors: Christoph
authors: C
authors: Bode
authors: Peter
authors: P
authors: Libby
authors: Karlheinz
authors: K
authors: Peter
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D023201:CD40 Ligand / Q000172:deficiency / Q000502:physiology*; D016466:CHO Cells; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002791:Cholesterol, Dietary / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D005487:Foam Cells / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008055:Lipids / Q000032:analysis; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012212:Rheology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002791:Cholesterol, Dietary; D008055:Lipids; D016177:Macrophage-1 Antigen; D011973:Receptors, LDL; D023201:CD40 Ligand; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate