Author + information
- Received July 15, 2017
- Revision received January 23, 2018
- Accepted January 26, 2018
- Published online April 2, 2018.
- Shuang Chen, MD, PhDa,b,
- Kenichi Shimada, PhDa,b,
- Timothy R. Crother, PhDa,b,
- Ebru Erbay, MD, PhDb,c,
- Prediman K. Shah, MDd and
- Moshe Arditi, MDa,b,∗ ()
- aDepartment of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California
- bDepartment of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, California
- cDepartment of Medicine, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
- dDivision of Cardiology, Oppenheimer Atherosclerosis Research Center, Cedars-Sinai Medical Center, Los Angeles, California
- ↵∗Address for correspondence:
Dr. Moshe Arditi, Division of Pediatric Infectious Diseases and Immunology, David Geffen School of Medicine at the University of California, Los Angeles, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 4221, Los Angeles, California 90048.
Background Recent studies indicate that Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling promote the development of high fat diet–induced atherosclerosis in hypercholesterolemic mice.
Objectives The authors investigated the role of TLR4/MyD88 signaling in hematopoietic and stromal cells in the development and infection-mediated acceleration of atherosclerosis.
Methods The authors generated bone marrow chimeras between wild-type and Tlr4–/– mice, as well as wild-type and Myd88–/– mice. All mice were on the Apoe–/– background and fed high fat diet. The authors infected the chimeric mice with C. pneumoniae (CP) and fed them high fat diet.
Results Aortic sinus plaques and lipid content were significantly reduced in Apoe–/– mice that received Tlr4–/–or Myd88–/– bone marrow compared with control animals despite similar cholesterol levels. Similarly, Tlr4 or Myd88 deficiency in stromal cells also led to a reduction in the lesion area and lipid in aortic sinus plaques. MyD88 expression only in CD11c+ dendritic cells (myeloid cells) in cells was sufficient in otherwise MyD88-deficient mice to induce CP infection–mediated acceleration of atherosclerosis, underlining the key role of MyD88 in CD11c+ dendritic cells (myeloid cells). Whereas CP infection markedly accelerated atherosclerosis in TLR4- or MyD88-positive chimeras, CP infection had a minimal effect on atherosclerosis in TLR4- or MyD88-deficient mice (either in the hematopoietic or stromal cell compartments).
Conclusions The authors show that both CP infection and metabolic stress associated with dyslipidemia use the same innate immune response pathway, utilizing TLR4/MyD88 signaling, with similar relative contributions in bone marrow–derived hematopoietic cells and in stromal cells. Further studies are required to understand this intricate and complex cross talk among innate and adaptive immune systems in various conditions to more effectively design dendritic cell–mediated atheroprotective vaccines and other therapeutic strategies.
- Chlamydia pneumoniae
- dendritic cells
- myeloid differentiation factor 88
- Toll-like receptor 4
This work was supported by National Institutes of Health grants HL66436-05 (to M.A.) and HL111483 (to S.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received July 15, 2017.
- Revision received January 23, 2018.
- Accepted January 26, 2018.
- 2018 American College of Cardiology Foundation
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