Experimental cell research · 2025
NOTCH signaling orchestrates the inflammatory-fibrotic continuum of macrophages in renal allograft rejection.
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Chen Yanxu, Zhang Qiang, Xie Wenyu, Gao Pengfei, Hu Zhaowei, Wu Shenghui, Bi Zirong, Zhang Huanxi, Gao Yifang, Wang Changxi, Liu Longshan
Аннотация
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.
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.