Chugh Rishi Man, Gupta-Saraf Pooja, Bhanja Payel, Saha Subhrajit
Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
J Transl Med. 2025 Sep 2;23(1):985. doi: 10.1186/s12967-025-07016-x.
BACKGROUND: Macrophages are essential for maintaining tissue homeostasis and accelerating the repair processes; however, their functionality can be severely compromised in pathological conditions such as radiation-induced dermatitis. In this study we analyzed the role of macrophage derived Vascular Endothelial Growth Factor (VEGF) on regulation of macrophage senescence and its role on radiation-induced skin damage. METHODS: We used bone marrow-derived macrophages (BMMɸ) isolated from Csf1r-iCre; VEGF (VEGF-null) and wild-type (WT) mice. Macrophages were exposed to oxidative and genotoxic stress using H₂O₂, doxorubicin, and radiation exposure to evaluate senescence. Senescence was assessed via SA-β-Gal staining and expression of senescence-related genes. Additionally, VEGF receptor inhibition in WT macrophages was performed to determine the role of VEGF/VEGFR signaling in senescence regulation. Phagocytosis and migration assays were conducted to evaluate functional differences. For in vivo analysis, WT and Csf1r-iCre; VEGF mice were exposed to radiation, and skin toxicity, histological changes, and senescence markers in skin macrophages were assessed. RESULTS: VEGF-null macrophages showed increased sensitivity to senescence, with elevated SA-β-Gal staining and upregulated senescence-associated gene expression. WT macrophages treated with a VEGF receptor inhibitor displayed increased senescence-associated markers expression, highlighting the importance of VEGF/VEGF-R signaling in preventing macrophage senescence-like phenotypes. Additionally, VEGF-null macrophages have reduced phagocytic and migratory abilities. Our in vivo study using Csf1r-iCre; VEGF mice showed more severe radiation-induced dermatitis, including increased skin toxicity, hyperkeratosis, and elevated senescence-associated markers in skin macrophages compared to WT controls. CONCLUSIONS: Absence of macrophage-derived VEGF leads to heightened macrophage dysfunction and exacerbates radiation-induced dermatitis. Targeting VEGF signaling may serve as a potential therapeutic strategy to mitigate radiation-related skin toxicity and improve patient outcomes during radiation therapy.
背景：巨噬细胞对于维持组织稳态和加速修复过程至关重要；然而，在诸如放射性皮炎等病理状况下，它们的功能可能会严重受损。在本研究中，我们分析了巨噬细胞衍生的血管内皮生长因子（VEGF）在调节巨噬细胞衰老中的作用及其在放射性皮肤损伤中的作用。 方法：我们使用从Csf1r-iCre;VEGF（VEGF基因缺失）小鼠和野生型（WT）小鼠分离的骨髓来源巨噬细胞（BMMɸ）。使用过氧化氢、阿霉素和辐射暴露使巨噬细胞暴露于氧化和基因毒性应激，以评估衰老。通过SA-β-Gal染色和衰老相关基因的表达评估衰老。此外，对WT巨噬细胞进行VEGF受体抑制，以确定VEGF/VEGFR信号在衰老调节中的作用。进行吞噬和迁移试验以评估功能差异。对于体内分析，将WT和Csf1r-iCre;VEGF小鼠暴露于辐射，并评估皮肤毒性、组织学变化以及皮肤巨噬细胞中的衰老标志物。 结果：VEGF基因缺失的巨噬细胞对衰老表现出更高的敏感性，SA-β-Gal染色增加且衰老相关基因表达上调。用VEGF受体抑制剂处理的WT巨噬细胞显示衰老相关标志物表达增加，突出了VEGF/VEGF-R信号在预防巨噬细胞衰老样表型中的重要性。此外，VEGF基因缺失的巨噬细胞吞噬和迁移能力降低。我们使用Csf1r-iCre;VEGF小鼠的体内研究表明，与WT对照相比，放射性皮炎更严重，包括皮肤毒性增加、角化过度以及皮肤巨噬细胞中衰老相关标志物升高。 结论：巨噬细胞衍生的VEGF缺失导致巨噬细胞功能障碍加剧，并加重放射性皮炎。靶向VEGF信号可能作为一种潜在的治疗策略，以减轻放疗期间与辐射相关的皮肤毒性并改善患者预后。
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