Spatially controlled tenascin-C accumulation contributes to inflammatory disease persistence in giant cell aortitis
Hui Shi1,2, Ying Tang1,3, Jing Li1,4
1Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Insights
Tissues from patients with giant cell aortitis (GCA) show Tenascin-C (TNC) accumulation, which drives inflammation via IL-6 signaling. Blocking IL-6 with tocilizumab reduced this inflammation, suggesting TNC as a therapeutic target for GCA.
Area of Science:
- Vascular Biology
- Immunology
- Pathology
Background:
- Giant cell aortitis (GCA) is a severe aortic inflammatory disease with poorly understood pathogenic mechanisms.
- Current understanding of GCA pathogenesis lacks detail on medial layer destruction and immune cell infiltration.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying aortic wall inflammation and remodeling in GCA.
- To identify key molecular players involved in GCA pathogenesis and persistence.
Main Methods:
- Imaging-based gene expression profiling of clinical GCA and IgG4-related aortitis samples.
- Single-cell spatial profiling to analyze aortic wall remodeling and cellular interactions.
- Histological confirmation of Tenascin-C (TNC) accumulation in diseased aortas.
- In vitro studies using primary human smooth muscle cells (SMCs) to investigate TNC-mediated signaling pathways (TLR4/NF-κB, IL-6/STAT3).
- Assessment of tocilizumab's efficacy in blocking TNC-driven inflammation.
Main Results:
- Significant aortic wall remodeling and stromal cell phenotypic modulation observed in GCA aortas.
- Expansion of Tenascin-C (TNC)-expressing stromal cells and localized TNC accumulation in inflammatory lesions.
- TNC promotes a pro-inflammatory phenotype in human SMCs, increasing IL-6 production via the TLR4/NF-κB pathway.
- IL-6 signaling propagates inflammation through STAT3 activation.
- Tocilizumab treatment effectively alleviated the TNC-induced pro-inflammatory phenotype.
Conclusions:
- Tenascin-C (TNC) plays a critical role in promoting and sustaining inflammation in giant cell aortitis.
- TNC-driven IL-6 signaling is a key mechanism perpetuating GCA pathogenesis.
- Targeting TNC or IL-6 signaling, such as with tocilizumab, represents a promising therapeutic strategy for achieving sustained remission in GCA.
Abstract:
Giant cell aortitis (GCA) is an inflammatory disease of the aortic wall with a characteristic giant cell pattern on pathology and can lead to life-threatening aortic aneurysm and dissection. Pathogenic GCA mechanisms underlying aortic inflammation and persistence remain elusive. Here, we demonstrate the complexity of medial layer destruction and immune cell infiltration in clinical granulomatous GCA and lymphoplasmacytic IgG4-related aortitis samples using imaging-based gene expression profiling. Single-cell spatial profiling revealed aortic wall remodeling in the GCA aortas, highlighting substantial phenotypic modulation in stromal cells, including vascular smooth muscle cells (SMCs) and fibroblasts. Specifically, we observed the expansion of stromal cells expressing Tenascin-C (TNC) mRNA and spatially refined TNC accumulation in lesion areas. We confirmed these findings histologically using diseased aortas resected from individuals with giant cell arteritis and clinically isolated aortitis. Mechanistically, our data suggest that TNC promotes a proinflammatory phenotype in primary human SMCs, elevating IL-6 levels partially through the TLR4/NF-κB pathway. IL-6 signaling propagates the proinflammatory loop by activating STAT3. Pharmacological blockade of the IL-6 receptor using tocilizumab alleviated the TNC-driven proinflammatory phenotype. We propose that TNC acts as a local catalyst of inflammatory disease persistence mainly via IL-6 signaling activation and offers a potential avenue for sustained disease remission.
Related Concept Videos
01:30Atherosclerosis I: Introduction
01:17Intracellular Signaling Affects Focal Adhesions
Some...