COL1A1-Enhanced CD44/SLC7A11 Interaction and Cystine Uptake Result in CD34 <sup>+</sup> Foam-Like Macrophage Accumulation in Transplant Arteriosclerosis
Abstract
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.
Article Details
Authors (21)
Junru Wu
College of Materials Science and Engineering Fuzhou University Fuzhou China
Tian He
Department of Molecular and Medical Pharmacology, University of California
Mengyao Qi
Clinical 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.).
Liang Chen
Meng Yao
State Key Laboratory of Advanced Chemical Power Sources, Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Engineering Research Center of High-efficiency Energy Storage (Ministry of Education), Frontiers Science Center for New Organic Matter (Ministry of Education), College of Chemistry
Xiexiong Zhao
Qiaoyu Zhou
Clinical 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.).
Wen Zhang
Xuewei Huang
CAS Key Laboratory of Nanosystem and Hierarchical Fabrication & CAS Center for Excellence in Nanoscience
Yuqing Liu
State Key Laboratory of Electronic Thin Films and Integrated Devices
Yingxuan Gong
Clinical 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.).
Tianrui Shi
Clinical 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.).
Yun Hong
Hang Gao
Chunyan Weng
Liping Peng
Qingzhong Xiao
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK (Q.X.).
Yao Lu
Hong Yuan
Clinical Laboratory Center, Central Hospital of Dalian University of Technology
Qingbo Xu
Jingjing Cai