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Updated: Aug 5, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
COL1A1-Enhanced CD44/SLC7A11 Interaction and Cystine Uptake Result in CD34+ Foam-Like Macrophage Accumulation in
Junru Wu1,2, Tian He3, Mengyao Qi1
1Clinical Research Center, Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China (J.W., M.Q., M.Y., X.Z., Q.Z., W.Z., X.H., Y.L., Y.G., T.S., C.W., L.P., Y.L., H.Y., J.C.).
Insights
Researchers identified a new type of inflammatory macrophage in transplant arteriosclerosis. Targeting collagen type 1 α1 (COL1A1), CD44, and solute carrier family 7 member 11 (SLC7A11) can reduce inflammation and improve graft survival.
Area of Science:
- Immunology
- Vascular Biology
- Transplantation
Background:
- Chronic transplant arteriosclerosis is a major cause of long-term graft failure.
- Targeting specific inflammatory macrophage subsets is crucial for controlling immune responses in allografts.
- Understanding macrophage origins and regulation in allograft arteriosclerosis is key for developing targeted therapies.
Purpose of the Study:
- To elucidate the origins and regulatory mechanisms of pro-inflammatory macrophages in allograft arteriosclerosis.
- To identify novel therapeutic targets for mitigating transplant arteriosclerosis.
Main Methods:
- Single-cell RNA sequencing and spatial transcriptomics on human and mouse allograft models.
- Flow cytometry and immunofluorescence to characterize macrophage subpopulations.
- Lineage tracing, depletion strategies, and in vitro/in vivo experiments to analyze cellular origins and molecular interactions.
- Analysis of COL1A1, CD44, and SLC7A11 interactions, metabolic profiling, and functional validation using inhibitors and knockout mice.
Main Results:
- A novel pro-inflammatory, foam-like macrophage phenotype was identified in allograft arterial adventitia, originating from CD34+ cells.
- Macrophage lipogenesis and inflammation are driven by increased cystine uptake via the CD44-SLC7A11 complex, activating mTORC1-HIF-1α signaling.
- Fibroblast-secreted COL1A1 anchors the CD44-SLC7A11 complex to the membrane, promoting macrophage activation.
- Inhibition of COL1A1, CD44, or SLC7A11 attenuated signaling, inflammation, lipogenesis, foam cell accumulation, and intimal hyperplasia.
Conclusions:
- Uncharacterized foam-like macrophages in transplant arteriosclerosis are regulated by COL1A1-enhanced amino acid metabolism.
- This pathway modulates lipogenesis and foam cell formation, presenting potential therapeutic targets to improve transplant outcomes.
Background:
Chronic transplant arteriosclerosis is the primary cause of long-term graft failure. Selectively targeting specific inflammatory macrophage subpopulations is essential for inhibiting the primary triggers of inflammatory and immune responses. Therefore, elucidating the origins and regulatory mechanisms of these macrophages in allograft arteriosclerosis is key for the development of targeted therapies.
Methods:
We performed single-cell RNA sequencing and spatial transcriptomics or integrated transcriptomic data from human chronic allograft vasculopathy specimens and mouse vascular allograft models. Flow cytometry and immunofluorescence staining were used to characterize macrophage subpopulations within remodeled allograft arteries. To determine cellular origins, CD34+ lineage tracing and depletion strategies were used. The interactions among COL1A1 (collagen type 1 α1), CD44, and SLC7A11 (solute carrier family 7 member 11) were analyzed using proximity ligation assays and coimmunoprecipitation. Furthermore, metabolic profiles were investigated with ultraperformance liquid chromatography coupled with high-resolution mass spectrometry. To validate the role of cystine transport in macrophage differentiation, we used pharmacologic inhibitors and a genetic approach using myeloid-specific Slc7a11 knockout mice (Lysm-Slc7a11-KO). The mechanisms identified in vivo were further corroborated through in vitro experiments.
Results:
We identified a novel proinflammatory foam-like macrophage phenotype in allograft arterial adventitia. These macrophages primarily originated from bone marrow-derived CD34+ lineage cells and exhibit heightened de novo lipogenesis and proinflammatory activity. Their lipogenesis is driven by increased cystine uptake, facilitated by enhanced membrane expression of the CD44-SLC7A11 complex, which activates mTORC1 (mechanistic target of rapamycin complex 1)-HIF-1α (hypoxia-inducible factor 1α) signaling. We also revealed that fibroblast-secreted COL1A1 is essential for anchoring the complex to the cell membrane through its direct interaction with CD44. Blocking COL1A1, CD44, or SLC7A11 effectively attenuated mTORC1-HIF-1α signaling, inflammation, and lipogenesis in macrophages as well as accumulation of foam-like cells and intimal hyperplasia in allograft arteries.
Conclusions:
This study has revealed previously uncharacterized foam-like macrophages in transplant arteriosclerosis, with COL1A1-enhanced amino acid metabolism modulating lipogenesis and foamy macrophage formation. This study offers potential therapeutic targets to modulate immune response and enhance transplant outcomes.
