2. Academic Validation
  3. NOTCH signaling orchestrates the inflammatory-fibrotic continuum of macrophages in renal allograft rejection

NOTCH signaling orchestrates the inflammatory-fibrotic continuum of macrophages in renal allograft rejection

  • Exp Cell Res. 2025 Oct 1;452(2):114711. doi: 10.1016/j.yexcr.2025.114711.
Yanxu Chen 1,  Qiang Zhang 1,  Wenyu Xie 1,  Pengfei Gao 2,  Zhaowei Hu 3,  Shenghui Wu 1,  Zirong Bi 1,  Huanxi Zhang 1,  Yifang Gao 4,  Changxi Wang 5,  Longshan Liu 6
Affiliations

Affiliations

  • 1 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, 510080, China.
  • 2 Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 3 Department of Orthopedics, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China.
  • 4 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, 510080, China. Electronic address: gaoyf26@sysu.edu.cn.
  • 5 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, 510080, China. Electronic address: wangchx@mail.sysu.edu.cn.
  • 6 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, 510080, China. Electronic address: liulshan@mail.sysu.edu.cn.
PMID: 40912393 DOI: 10.1016/j.yexcr.2025.114711
Abstract

Background: Chronic rejection is a major cause of long-term kidney allograft failure, characterized by persistent inflammation and progressive fibrosis. Macrophages are central mediators of this process, but their phenotypic heterogeneity and regulatory mechanisms in chronic rejection remain incompletely understood.

Methods: We performed single-cell transcriptomic analysis on renal allograft biopsies from patients with different types of rejection and on a time-course rat model of chronic rejection. Macrophage subsets were identified through transcriptional profiling and Pseudotime trajectory analysis. Ligand-receptor analysis defined upstream intercellular communication, while in vitro assays using THP-1 macrophages evaluated responses to Jagged1 stimulation under polarizing conditions.

Results: A distinct TGFB+CD86+ macrophage subset exhibiting both pro-inflammatory and pro-fibrotic features was identified. This population, enriched in mixed rejection, occupied an intermediate position along the inferred macrophage trajectory and displayed dual ontogeny. It received Jagged1-NOTCH2 signals from mesenchymal-transitioned tubular epithelial cells and inflammatory inputs from infiltrating T cells. In vitro, co-stimulation with soluble Jagged1 under M1-polarizing conditions induced a similar hybrid phenotype. In the rat model, a phenotypically comparable subset, provisionally termed M2b, appeared early post-transplantation and was later replaced by M2a macrophages as fibrosis progressed. Ligand-receptor analysis confirmed conserved Jagged1-NOTCH2 signaling regulatory axis in vivo.

Conclusion: In summary, we identify a transitional TGFB+CD86+ macrophage population governed by JAG1-NOTCH2 signaling, bridging immune activation and fibrotic remodeling. Modulating this pathway may offer a therapeutic approach to reshape macrophage differentiation and mitigate chronic rejection.

Keywords

Chronic rejection; Fibrosis; Kidney transplant; Macrophage; NOTCH.

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