B-cell aortic homing and atheroprotection depend on Id3.
BACKGROUND
B cells are abundant in the adventitia of normal and diseased vessels. Yet, the molecular and cellular mechanisms mediating homing of B cells to the vessel wall and B-cell effects on atherosclerosis are poorly understood. Inhibitor of differentiation-3 (Id3) is important for atheroprotection in mice and polymorphism in the human ID3 gene has been implicated as a potential risk marker of atherosclerosis in humans. Yet, the role of Id3 in B-cell regulation of atherosclerosis is unknown.


OBJECTIVE
To determine if Id3 regulates B-cell homing to the aorta and atheroprotection and identify molecular and cellular mechanisms mediating this effect.


RESULTS
Loss of Id3 in Apoe(-/-) mice resulted in early and increased atherosclerosis. Flow cytometry revealed a defect in Id3(-/-) Apoe(-/-) mice in the number of B cells in the aorta but not the spleen, lymph nodes, and circulation. Similarly, B cells transferred from Id3(-/-) Apoe(-/-) mice into B-cell-deficient mice reconstituted spleen, lymph node, and blood similarly to B cells from Id3(+/+) Apoe(-/-) mice, but aortic reconstitution and B-cell-mediated inhibition of diet-induced atherosclerosis was significantly impaired. In addition to retarding initiation of atherosclerosis, B cells homed to regions of existing atherosclerosis, reduced macrophage content in plaque, and attenuated progression of disease. The chemokine receptor CCR6 was identified as an important Id3 target mediating aortic homing and atheroprotection.


CONCLUSIONS
Together, these results are the first to identify the Id3-CCR6 pathway in B cells and demonstrate its role in aortic B-cell homing and B-cell-mediated protection from early atherosclerosis.
University of Virginia, PO Box 801394, 415 Lane Rd, Charlottesville, VA 22908, USA. cam8c@virginia.edu
Amanda C
AC
Doran
Michael J
MJ
Lipinski
Stephanie N
SN
Oldham
James C
JC
Garmey
Kirsti A
KA
Campbell
Marcus D
MD
Skaflen
Alexis
A
Cutchins
Daniel J
DJ
Lee
David K
DK
Glover
Kimberly A
KA
Kelly
Elena V
EV
Galkina
Klaus
K
Ley
Joseph L
JL
Witztum
Sotirios
S
Tsimikas
Timothy P
TP
Bender
Coleen A
CA
McNamara
D000818:Animals; D001011:Aorta / Q000473:pathology* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000473:pathology* / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D015994:Incidence; D051796:Inhibitor of Differentiation Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000503:physiopathology; D054399:Receptors, CCR6 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D001057:Apolipoproteins E; C498126:CCR6 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D054399:Receptors, CCR6; C067679:Idb3 protein, mouse