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

by Selleckchem | Dec 08 2023

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, Cd74high 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.

Comments:

Your description provides a detailed overview of the research conducted on thoracic aortic aneurysm and dissection (TAAD) using a mouse model and single-cell RNA sequencing. Here's a summary of the key findings and implications of the study:

### Key Findings:

1. **Pathogenesis Understanding:**
- TAAD involves degeneration of the thoracic aorta's medial layer.
- Stress-responsive and Toll-like receptor signaling pathways are excessively activated, leading to smooth muscle cell senescence at the early stage of TAAD.

2. **Cellular Diversity:**
- **Aortic Macrophages:** Three distinct subpopulations of aortic macrophages were identified: Lyve1+ resident-like, Cd74high antigen-presenting, and Il1rn+/Trem1+ pro-inflammatory macrophages.

3. **Dominant Inflammatory Source:**
- The pro-inflammatory macrophage subpopulation (Il1rn+/Trem1+) was identified as the primary source of detrimental molecules in both mice and humans.

4. **Therapeutic Interventions:**
- **Ki20227:** Suppressing macrophage accumulation in the aorta with Ki20227 decreased the incidence of TAAD and aortic rupture in mice.
- **mLR12:** Targeting the Il1rn+/Trem1+ macrophage subpopulation through Trem1 blockade with mLR12 significantly decreased the aortic rupture rate in mice.

### Implications:

1. **Anti-Inflammation Therapy:** The study highlights the importance of anti-inflammatory therapy in treating TAAD, suggesting that controlling inflammation could be a key therapeutic strategy.

2. **Macrophage Subpopulation Targeting:** Pinpointing the Il1rn+/Trem1+ macrophage subpopulation as the major source of detrimental molecules suggests a specific target for therapy. Blockade of Trem1 using mLR12 represents a promising medical treatment avenue.

3. **Clinical Relevance:** The findings in mice and humans provide valuable insights into the potential translation of these therapies to clinical settings for TAAD patients.

In summary, your research provides a deep understanding of the molecular and cellular changes in TAAD development, offering specific targets for therapeutic intervention. The identification of the Il1rn+/Trem1+ macrophage subpopulation as a key player underscores the potential of targeted therapies in managing this life-threatening condition.