Open AccessInhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome
Author(s) -
Hironori Hara,
Sonoko Maemura,
Takayuki Fujiwara,
Norifumi Takeda,
Satoshi Ishii,
Hiroki Yagi,
Takaaki Suzuki,
Mutsuo Harada,
Haruhiro Toko,
Tsubasa Kanaya,
Hideaki Ijichi,
Harold L. Moses,
Eiki Takimoto,
Hiroyuki Morita,
Hiroshi Akazawa,
Issei Komuro
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0239908
Subject(s) - marfan syndrome , transforming growth factor , microbiology and biotechnology , aorta , transforming growth factor beta , aortic aneurysm , adventitia , pathophysiology , myeloid , signal transduction , chemistry , medicine , immunology , biology
Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1 C1039G/+ MFS mice ( Fbn1 C1039G/+ ; LysM-Cre/+ ; Tgfbr2 fl/fl mice, hereinafter called Fbn1 C1039G/+ ; Tgfbr2 MyeKO ) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1 C1039G/+ ; Tgfbr2 MyeKO mice. In the aorta of Fbn1 C1039G/+ ; Tgfbr2 MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro , TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.