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CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1.
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- Additional Information
- Source:
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE
- Publication Information:
Publication: Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: [Dallas, Tex., etc., American Heart Association, etc.]
- Subject Terms:
Atherosclerosis/
*etiology ;
CD40 Ligand/
*physiology ;
Inflammation/
*etiology ;
Macrophage-1 Antigen/
*physiology;
Animals ;
Aorta, Thoracic/
chemistry ;
Aorta, Thoracic/
pathology ;
Aortic Diseases/
etiology ;
Aortic Diseases/
pathology ;
Atherosclerosis/
genetics ;
Atherosclerosis/
physiopathology ;
Atherosclerosis/
prevention & control ;
CD40 Ligand/
deficiency ;
CHO Cells ;
Chemotaxis, Leukocyte/
physiology ;
Cholesterol, Dietary/
toxicity ;
Cricetinae ;
Cricetulus ;
Crosses, Genetic ;
Diet, Atherogenic ;
Foam Cells/
pathology ;
Genetic Predisposition to Disease ;
Humans ;
Inflammation/
genetics ;
Inflammation/
physiopathology ;
Lipids/
analysis ;
Macrophages/
pathology ;
Mice ;
Mice, Inbred C57BL ;
Mice, Knockout ;
Models, Biological ;
Monocytes/
drug effects ;
Monocytes/
enzymology ;
Peritonitis/
chemically induced ;
Peritonitis/
metabolism ;
Peritonitis/
pathology ;
Peroxidase/
metabolism ;
Receptors, LDL/
deficiency ;
Receptors, LDL/
genetics ;
Rheology ;
Tetradecanoylphorbol Acetate/
pharmacology - 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.
- Grant Information:
HL-66086 United States HL NHLBI NIH HHS; HL34636 United States HL NHLBI NIH HHS
- Accession Number:
0 (Cholesterol, Dietary)
0 (Lipids)
0 (Macrophage-1 Antigen)
0 (Receptors, LDL)
147205-72-9 (CD40 Ligand)
EC 1.11.1.7 (Peroxidase)
NI40JAQ945 (Tetradecanoylphorbol Acetate)
- Publication Date:
Date Created: 20070321 Date Completed: 20070529 Latest Revision: 20211109
- Publication Date:
20240829
- Accession Number:
10.1161/CIRCULATIONAHA.106.683201
- Accession Number:
17372166
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