Spatiotemporal Immune-Fibroblast Crosstalk in Pulmonary Fibrosis: From Failed Repair to Fibrotic Niche Formation.
5 affiliations
- 1The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Biomedical Basic Research Center of Jiangsu, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
- 2Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome 00133, Italy.
- 3Laboratory Animal Center, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
- 4Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
- 5MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
Abstract
Pulmonary fibrosis is a common and often fatal outcome of fibrosing interstitial lung diseases, characterized by progressive extracellular matrix deposition, destruction of alveolar architecture and irreversible loss of respiratory function. Although fibroblast activation and epithelial dysfunction are central to disease pathogenesis, fibrosis cannot be adequately explained by mesenchymal dysregulation alone. Rather, it represents a failure of multicellular repair regulation, in which immune cells, fibroblasts and epithelial populations reciprocally reshape cellular states, tissue niches and disease trajectories. Early innate immune responses amplify epithelial injury while simultaneously initiating provisional repair; however, when injury persists, these transient programmes fail to resolve and become stabilized into chronic profibrotic circuits involving monocyte-derived macrophages, dysfunctional T cells, inflammatory fibroblasts and matrix-producing myofibroblasts. Recent single-cell, spatial transcriptomic and lineage-tracing studies have revealed discrete cellular states, including SPP1⁺ scar-associated macrophages, inflammatory fibroblasts, CTHRC1⁺ myofibroblasts and tertiary-lymphoid-structure-associated stromal cells, that assemble multicellular, stage-specific and microanatomically restricted fibrotic niches. Collectively, these findings support a model in which soluble mediators, extracellular matrix mechanics, metabolic rewiring and immune-regulatory signalling cooperate to establish self-reinforcing stromal-immune circuits. In this Review, we synthesize current evidence for bidirectional immune-fibroblast crosstalk in pulmonary fibrosis, focusing on macrophage and T cell programmes, fibroblast-mediated immune regulation, spatiotemporal niche remodelling, mechanistic signalling networks, experimental models and therapeutic opportunities. We propose that progressive fibrosis reflects the spatiotemporal locking of pathological epithelial-immune-stromal circuits, a framework that may explain the limited efficacy of broad anti-inflammatory therapies in idiopathic pulmonary fibrosis and guide the development of more precise, stage-specific and combinatorial antifibrotic strategies.
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BibTeX
@article{lu2026spatiotemporal,
title = {{Spatiotemporal Immune-Fibroblast Crosstalk in Pulmonary Fibrosis: From Failed Repair to Fibrotic Niche Formation.}},
author = {Simeng Lu and Weijia Zhang and Xiaoming Zhao and Chao Feng and Wangwang Chen and Yufang Shi and Jiankai Fang},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.137072},
url = {https://europepmc.org/article/MED/42909980},
note = {CC BY},
}
RIS
TY - JOUR
TI - Spatiotemporal Immune-Fibroblast Crosstalk in Pulmonary Fibrosis: From Failed Repair to Fibrotic Niche Formation.
AU - Simeng Lu
AU - Weijia Zhang
AU - Xiaoming Zhao
AU - Chao Feng
AU - Wangwang Chen
AU - Yufang Shi
AU - Jiankai Fang
PY - 2026
DA - 2026/09/24
JO - International journal of biological sciences
DO - 10.7150/ijbs.137072
UR - https://europepmc.org/article/MED/42909980
AB - Pulmonary fibrosis is a common and often fatal outcome of fibrosing interstitial lung diseases, characterized by progressive extracellular matrix deposition, destruction of alveolar architecture and irreversible loss of respiratory function. Although fibroblast activation and epithelial dysfunction are central to disease pathogenesis, fibrosis cannot be adequately explained by mesenchymal dysregulation alone. Rather, it represents a failure of multicellular repair regulation, in which immune cells, fibroblasts and epithelial populations reciprocally reshape cellular states, tissue niches and disease trajectories. Early innate immune responses amplify epithelial injury while simultaneously initiating provisional repair; however, when injury persists, these transient programmes fail to resolve and become stabilized into chronic profibrotic circuits involving monocyte-derived macrophages, dysfunctional T cells, inflammatory fibroblasts and matrix-producing myofibroblasts. Recent single-cell, spatial transcriptomic and lineage-tracing studies have revealed discrete cellular states, including SPP1⁺ scar-associated macrophages, inflammatory fibroblasts, CTHRC1⁺ myofibroblasts and tertiary-lymphoid-structure-associated stromal cells, that assemble multicellular, stage-specific and microanatomically restricted fibrotic niches. Collectively, these findings support a model in which soluble mediators, extracellular matrix mechanics, metabolic rewiring and immune-regulatory signalling cooperate to establish self-reinforcing stromal-immune circuits. In this Review, we synthesize current evidence for bidirectional immune-fibroblast crosstalk in pulmonary fibrosis, focusing on macrophage and T cell programmes, fibroblast-mediated immune regulation, spatiotemporal niche remodelling, mechanistic signalling networks, experimental models and therapeutic opportunities. We propose that progressive fibrosis reflects the spatiotemporal locking of pathological epithelial-immune-stromal circuits, a framework that may explain the limited efficacy of broad anti-inflammatory therapies in idiopathic pulmonary fibrosis and guide the development of more precise, stage-specific and combinatorial antifibrotic strategies.
SN - 1449-2288
ER -