Radiation‐induced AXL upregulation in CCR2+ monocytes promotes cardiac fibrosis
5 affiliations
- 1Sun Yat‐sen University Cancer Centre
- 2The First Affiliated Hospital Sun Yat‐sen University
- 3The First Affiliated Hospital of Sun Yat‐sen University
- 4Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University
- 5Hainan General Hospital (Hainan Affiliated Hospital of Medical University)
Abstract
Background Thoracic radiotherapy can cause delayed cardiac fibrosis, but the immune mechanisms linking radiation injury to fibroblast activation remain unclear. We investigated whether CCR2+ monocytes contribute to radiation‐induced cardiac fibrosis and whether AXL regulates their fibroblast‐activating activity. Methods and materials C57BL/6 mice received 20 Gy whole‐thorax irradiation, and remodelling was assessed from IR_D0 to IR_D60. Bulk RNA sequencing was integrated with single‐cell datasets and CIBERSORTx deconvolution, lineage tracing, and tissue staining. CCR2+ monocyte function was examined by CCR2 neutralisation, and circulating CCR2+Ly6Cʰi monocytes were quantified by flow cytometry. AXL was investigated using inducible myeloid Axl deletion and bemcentinib (R428). MAPK signalling was assessed by transcriptomic analysis and immunoblotting of sorted CCR2+Ly6Cʰi monocytes. Conditioned medium from sorted monocytes after Axl deletion, AXL inhibition with R428, or MEK1/2 inhibition with U0126 was applied to cardiac fibroblasts. Results Cardiac fibrosis was established by IR_D30, while leukocyte infiltration and apoptotic signals remained above baseline. Transcriptomic analyses and lineage tracing showed increased cardiac accumulation of CCR2+ monocytes. CCR2 neutralisation reduced circulating CCR2+Ly6Cʰi monocytes and attenuated interstitial collagen deposition and fibrotic marker expression. Axl was enriched in the CCR2+ monocyte compartment. Myeloid Axl deletion and R428 reduced cardiac fibrosis. Axl deletion suppressed MAPK‐related transcriptional programs, whereas genetic or pharmacological AXL targeting reduced MEK and ERK phosphorylation in sorted monocytes. Conditioned medium from IR_D30 monocytes induced COL1A1 and α‐SMA expression in fibroblasts, and this effect was reduced by Axl deletion, R428, or U0126 treatment of donor monocytes. Conclusions AXL signalling contributes to the fibroblast‐activating paracrine activity of cardiac CCR2+ monocytes after irradiation, at least in part through MEK/ERK signalling. Key points Radiation exposure induces cardiac fibrosis through immunestromal interactions. CCR2+ monocytes promote fibroblast activation during radiation-induced cardiac fibrosis. AXL regulates monocyte‐mediated fibroblast activation through MEK/ERK signaling. Targeting the AXL‐MEK/ERK pathway may provide a potential strategy for preventing radiation‐induced cardiac fibrosis.
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BibTeX
@article{li2026radiationinduced,
title = {{Radiation‐induced AXL upregulation in CCR2+ monocytes promotes cardiac fibrosis}},
author = {Ying‐Yi Li and Jian‐Qi Xiong and Zhi‐Hui Zhang and Xin Liu and Yi‐Xin Cheng and Yong‐Xin Chi and Guan‐Qiao Li and Wen‐Huan Zhong and Shuang Chen and Zhen‐Yu He},
journal = {Clinical and translational medicine},
year = {2026},
month = oct,
doi = {10.1002/ctm2.70852},
url = {https://europepmc.org/article/PMC/PMC13659278},
note = {CC BY},
}
RIS
TY - JOUR
TI - Radiation‐induced AXL upregulation in CCR2+ monocytes promotes cardiac fibrosis
AU - Ying‐Yi Li
AU - Jian‐Qi Xiong
AU - Zhi‐Hui Zhang
AU - Xin Liu
AU - Yi‐Xin Cheng
AU - Yong‐Xin Chi
AU - Guan‐Qiao Li
AU - Wen‐Huan Zhong
AU - Shuang Chen
AU - Zhen‐Yu He
PY - 2026
DA - 2026/10/01
JO - Clinical and translational medicine
DO - 10.1002/ctm2.70852
UR - https://europepmc.org/article/PMC/PMC13659278
AB - Background Thoracic radiotherapy can cause delayed cardiac fibrosis, but the immune mechanisms linking radiation injury to fibroblast activation remain unclear. We investigated whether CCR2+ monocytes contribute to radiation‐induced cardiac fibrosis and whether AXL regulates their fibroblast‐activating activity. Methods and materials C57BL/6 mice received 20 Gy whole‐thorax irradiation, and remodelling was assessed from IR_D0 to IR_D60. Bulk RNA sequencing was integrated with single‐cell datasets and CIBERSORTx deconvolution, lineage tracing, and tissue staining. CCR2+ monocyte function was examined by CCR2 neutralisation, and circulating CCR2+Ly6Cʰi monocytes were quantified by flow cytometry. AXL was investigated using inducible myeloid Axl deletion and bemcentinib (R428). MAPK signalling was assessed by transcriptomic analysis and immunoblotting of sorted CCR2+Ly6Cʰi monocytes. Conditioned medium from sorted monocytes after Axl deletion, AXL inhibition with R428, or MEK1/2 inhibition with U0126 was applied to cardiac fibroblasts. Results Cardiac fibrosis was established by IR_D30, while leukocyte infiltration and apoptotic signals remained above baseline. Transcriptomic analyses and lineage tracing showed increased cardiac accumulation of CCR2+ monocytes. CCR2 neutralisation reduced circulating CCR2+Ly6Cʰi monocytes and attenuated interstitial collagen deposition and fibrotic marker expression. Axl was enriched in the CCR2+ monocyte compartment. Myeloid Axl deletion and R428 reduced cardiac fibrosis. Axl deletion suppressed MAPK‐related transcriptional programs, whereas genetic or pharmacological AXL targeting reduced MEK and ERK phosphorylation in sorted monocytes. Conditioned medium from IR_D30 monocytes induced COL1A1 and α‐SMA expression in fibroblasts, and this effect was reduced by Axl deletion, R428, or U0126 treatment of donor monocytes. Conclusions AXL signalling contributes to the fibroblast‐activating paracrine activity of cardiac CCR2+ monocytes after irradiation, at least in part through MEK/ERK signalling. Key points Radiation exposure induces cardiac fibrosis through immunestromal interactions. CCR2+ monocytes promote fibroblast activation during radiation-induced cardiac fibrosis. AXL regulates monocyte‐mediated fibroblast activation through MEK/ERK signaling. Targeting the AXL‐MEK/ERK pathway may provide a potential strategy for preventing radiation‐induced cardiac fibrosis.
SN - 2001-1326
ER -