Radiation-induced AXL upregulation in CCR2⁺ monocytes promotes cardiac fibrosis.

Authors

Ying-Yi Li, Jian-Qi Xiong, Zhi-Hui Zhang, Xin Liu, Yi-Xin Cheng, Yong-Xin Chi, Guan-Qiao Li, Wen-Huan Zhong, Shuang Chen, Zhen-Yu He

Published in

Clinical and translational medicine. Volume 16. Issue 10. Pages e70852.

Abstract

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.
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.
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.
AXL signalling contributes to the fibroblast-activating paracrine activity of cardiac CCR2⁺ monocytes after irradiation, at least in part through MEK/ERK signalling.
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.

PMID:
42865139
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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