Clinical and translational medicine · 2026
Radiation-induced AXL upregulation in CCR2+ monocytes promotes cardiac fibrosis.
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Li Ying-Yi, Xiong Jian-Qi, Zhang Zhi-Hui, Liu Xin, Cheng Yi-Xin, Chi Yong-Xin, Li Guan-Qiao, Zhong Wen-Huan, Chen Shuang, He Zhen-Yu
Аннотация
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.
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.