Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome.

Hironori Hara,Takaaki Suzuki,Harold L Moses,Eiki Takimoto,Hiroyuki Morita,Hiroki Yagi,Haruhiro Toko,Takayuki Fujiwara,Mutsuo Harada,Sonoko Maemura,Issei Komuro,Norifumi Takeda,Hideaki Ijichi,Satoshi Ishii,Hiroshi Akazawa,Tsubasa Kanaya,Tohru Minamino

doi:10.1371/journal.pone.0239908

Hironori Hara, Takaaki Suzuki + Show 15 more

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https://doi.org/10.1371/journal.pone.0239908

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Journal: PloS one	Publication Date: Nov 11, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: University of Tokyo Hospital, Vanderbilt University

Abstract

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 Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) 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 Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO 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.

Highlights

Marfan syndrome (MFS) is a systemic disorder of connective tissues caused by pathogenic variants in the FBN1 gene, which encodes the major component of the extracellular matrix microfibril fibrillin-1 [1]
To examine the impact of transforming growth factor-β (TGF-β) signaling in myeloid cells on aortic aneurysmal formation in MFS, we ablated Tgfbr2 in myeloid cells in Fbn1C1039G/+ heterozygous MFS mice by crossing with myeloid-specific Tgfbr2 knockout mice (Tgfbr2MyeKO mice)
These findings suggest that TGF-β signaling in myeloid cells is inessential in normal aortic development and homeostasis but it promotes the progression of aortic aneurysmal formation in MFS

Summary

Introduction

MFS is a systemic disorder of connective tissues caused by pathogenic variants in the FBN1 gene, which encodes the major component of the extracellular matrix microfibril fibrillin-1 [1]. Fibrillin-1 binds to the latent complex of TGF-β and regulates its activity in response to pathophysiological stresses. FBN1 pathogenic variants that affect the structure or function of fibrillin-1 protein cause structural weakness of the connective tissue and stimulate improper latent TGF-β activation [2, 3]. Among the diverse manifestations of MFS, aortic aneurysm and dissection are the most serious and the leading causes of death [4].

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