Single-cell RNA sequencing identifies an Il1rn+/Trem1+ macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection

Xuanyu Liu; Wen Chen; Guoyan Zhu; Hang Yang; Wenke Li; Mingyao Luo; Chang Shu; Zhou Zhou

doi:10.1038/s41421-021-00362-2

Single-cell RNA sequencing identifies an Il1rn⁺/Trem1⁺ macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection

Cell Discov. 2022 Feb 8;8(1):11. doi: 10.1038/s41421-021-00362-2.

Authors

Xuanyu Liu^#^{1

2}, Wen Chen^#^{1

2}, Guoyan Zhu^#^{1

2}, Hang Yang^{1

2}, Wenke Li^{1

2}, Mingyao Luo^{1

3

4}, Chang Shu^{5

6}, Zhou Zhou^{7

8}

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, Beijing, China.
³ Center of Vascular Surgery, Fuwai Hospital, Beijing, China.
⁴ Department of Vascular Surgery, Fuwai Yunnan Cardiovascular Hospital, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan, China.
⁵ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. changshu@vip.126.com.
⁶ Center of Vascular Surgery, Fuwai Hospital, Beijing, China. changshu@vip.126.com.
⁷ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhouzhou@fuwaihospital.org.
⁸ Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, Beijing, China. zhouzhou@fuwaihospital.org.

^# Contributed equally.

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition characterized by medial layer degeneration of the thoracic aorta. A thorough understanding of the regulator changes during pathogenesis is essential for medical therapy development. To delineate the cellular and molecular changes during the development of TAAD, we performed single-cell RNA sequencing of thoracic aortic cells from β-aminopropionitrile-induced TAAD mouse models at three time points that spanned from the early to the advanced stages of the disease. Comparative analyses were performed to delineate the temporal dynamics of changes in cellular composition, lineage-specific regulation, and cell-cell communications. Excessive activation of stress-responsive and Toll-like receptor signaling pathways contributed to the smooth muscle cell senescence at the early stage. Three subpopulations of aortic macrophages were identified, i.e., Lyve1⁺ resident-like, Cd74^high antigen-presenting, and Il1rn⁺/Trem1⁺ pro-inflammatory macrophages. In both mice and humans, the pro-inflammatory macrophage subpopulation was found to represent the predominant source of most detrimental molecules. Suppression of macrophage accumulation in the aorta with Ki20227 could significantly decrease the incidence of TAAD and aortic rupture in mice. Targeting the Il1rn⁺/Trem1⁺ macrophage subpopulation via blockade of Trem1 using mLR12 could significantly decrease the aortic rupture rate in mice. We present the first comprehensive analysis of the cellular and molecular changes during the development of TAAD at single-cell resolution. Our results highlight the importance of anti-inflammation therapy in TAAD, and pinpoint the macrophage subpopulation as the predominant source of detrimental molecules for TAAD. Targeting the IL1RN⁺/TREM1⁺ macrophage subpopulation via blockade of TREM1 may represent a promising medical treatment.

Abstract

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