Probes for IL1RN

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.

Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness, indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.