Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice

Zenghui Zhang; Maoxiong Wu; Lei Yao; Weibin Zhou; Xiao Liu; Zhiteng Chen; Ping Hua; Leibo Xu; Lei Lv; Chiyu Liu; Chunling Huang; Sixu Chen; Zhaoqi Huang; Yuna Huang; Jiaqi He; Tingfeng Chen; Jingfeng Wang; Woliang Yuan; Zhaoyu Liu; Yangxin Chen

doi:10.1161/ATVBAHA.124.321429

Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice

Arterioscler Thromb Vasc Biol. 2024 Nov 7. doi: 10.1161/ATVBAHA.124.321429. Online ahead of print.

Authors

Zenghui Zhang^#^{1

2

3

4

5}, Maoxiong Wu^#^{1

2

3

4}, Lei Yao^#², Weibin Zhou^{1

2

3

4}, Xiao Liu^{1

2

3

4}, Zhiteng Chen^{1

2

3

4}, Ping Hua⁶, Leibo Xu⁷, Lei Lv⁸, Chiyu Liu^{1

2

3

4}, Chunling Huang², Sixu Chen^{1

2

3

4}, Zhaoqi Huang^{1

2

3

4}, Yuna Huang^{1

2

3

4}, Jiaqi He^{1

2

3

4}, Tingfeng Chen^{1

2

3

4}, Jingfeng Wang^{1

2

3

4}, Woliang Yuan^{1

2

3

4}, Zhaoyu Liu², Yangxin Chen^{1

2

3

4}

Affiliations

¹ Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (Z.Z., M.W., W.Z., X.L., Z.C., C.L., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Y.C.).
² Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (Z.Z., M.W., L.Y., W.Z., X.L., Z.C., C.L., C.H., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Z.L., Y.C.).
³ Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (Z.Z., M.W., W.Z., X.L., Z.C., C.L., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Y.C.).
⁴ Guangzhou Key Laboratory of Molecular Mechanism and Translation in Major Cardiovascular Disease, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (Z.Z., M.W., W.Z., X.L., Z.C., C.L., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Y.C.).
⁵ Department of Cardiology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China (Z.Z.).
⁶ Department of Cardio-Vascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (P.H.).
⁷ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (L.X.).
⁸ Department of Cardiac and Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Yunnan, China (L.L.).

^# Contributed equally.

PMID: 39508103
DOI: 10.1161/ATVBAHA.124.321429

Abstract

Background: The development of aortic dissection (AD) is closely associated with inflammation. The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) signaling pathway critically regulates innate immunity and has emerged as an important target in cardiovascular diseases; however, its role in AD remains unclear.

Methods: Transcriptome data from human and mouse ADs were used to perform differentially expressed gene-based protein-protein interaction network analyses. Tyrobp knockout (Tyrobp^-/-), myeloid cell-specific Tyrobp^-/- (Tyrobp^fl/fl Lyz2^cre), and Trem2 knockout (Trem2^-/^-) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in Tyrobp deficiency-mediated AD progression, macrophages were depleted using clodronate liposomes. Bulk and single-cell RNA sequencing, immunofluorescence staining, and quantitative real-time polymerase chain reaction were performed to assess inflammation and the underlying mechanisms of Tyrobp in AD.

Results: Network analysis identified Tyrobp as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell-specific deficiency of Tyrobp in mice significantly increased AD incidence and exacerbated extracellular matrix degradation and macrophage infiltration within the aortic wall. Macrophage depletion mitigated the adverse effects of Tyrobp deficiency on AD progression. Additionally, Tyrobp deficiency enhanced TLR (Toll-like receptor)-4 signaling and macrophage activation, which were abrogated by TLR4 inhibitors. Furthermore, deletion of the Tyrobp-associated receptor Trem2 significantly aggravated mouse AD development, whereas Trem2 agonist treatment conferred protection against AD.

Conclusions: Our findings suggest a novel role for the Trem2/Tyrobp axis in AD development in mice. Enhancement of Trem2/Tyrobp signaling may represent a promising strategy for the prevention and treatment of AD. Future studies to clarify the role of Trem2/Tyrobp in human AD are warranted.

Keywords: aortic dissection; incidence; inflammation; liposomes; macrophages.