Response of human macrophages to gamma radiation is mediated via expression of endogenous retroviruses

Ionizing radiation (IR) induces recruitment of monocytes into the exposed area where they are differentiated into macrophages, which elicit an inflammatory response to IR, but can also facilitate vascular growth and tumor progression by producing anti-inflammatory factors. Using primary human monocyte-derived macrophages (MDM) and the THP1 monocytic cell line, we demonstrated that therapeutically relevant gamma radiation doses triggered monocyte differentiation into macrophages with increased expression of both pro- and anti-inflammatory markers, induction of type I interferons (IFN-I), activation of their receptor IFNAR1, and expression of IFN-stimulated genes. We found that these changes correlate with significantly upregulated expression of 622 retroelements from various groups, particularly of several clades of human endogenous retroviruses (HERVs). Elevated transcription was detected in both sense and antisense directions in the HERV subgroups tested, including the most genetically homogeneous clade HERVK HML-2. This resulted in formation of long dsRNA bound to the dsRNA sensors MDA5 and TLR3 and triggering signaling pathways resulted in increased expression of IFN-I and inflammation related genes that enhanced the cumulative inflammatory effect of radiation-induced senescence. HML-2 knockdown was accompanied with reduced expression and secretion of IFNα, pro-inflammatory (IL-1β, IL-6, CCL2, CCL3, CCL8, and CCL20) and anti-inflammatory (IL10) modulators in irradiated monocytes and MDMs. We conclude that radiation stress-induced HERV expression enhances the IFN-I and cytokine response and results in increased levels of pro-inflammatory modulators along with expression of anti-inflammatory factors associated with the macrophage tumorigenic phenotype.

电离辐射（Ionizing radiation, IR）可诱导单核细胞募集至受照区域，并在此分化为巨噬细胞。巨噬细胞既能对电离辐射产生炎症应答，亦可通过分泌抗炎因子促进血管生成与肿瘤进展。本研究采用原代人单核细胞源性巨噬细胞（MDM）与THP1单核细胞系，证实治疗相关剂量的γ辐射可触发单核细胞向巨噬细胞分化，同时上调促炎与抗炎标志物的表达、诱导I型干扰素（IFN-I）的产生、激活其受体干扰素α/β受体1（IFNAR1），并促进干扰素刺激基因的表达。研究发现，上述变化与622种不同类别的逆转录元件的表达显著上调相关，其中尤以多个人类内源性逆转录病毒（HERVs）进化枝的上调最为显著。在所检测的HERV亚组中，包括遗传均质性最高的HERVK HML-2进化枝在内，均可检测到有义链与反义链的转录水平升高。该现象可形成长双链RNA（dsRNA），并与dsRNA感受器黑素瘤分化相关蛋白5（MDA5）及Toll样受体3（TLR3）结合，进而激活信号通路，最终上调I型干扰素及炎症相关基因的表达，放大辐射诱导衰老的累积炎症效应。敲低HML-2可降低受照单核细胞与MDM中干扰素α、促炎调节因子（IL-1β、IL-6、CCL2、CCL3、CCL8及CCL20）以及抗炎调节因子IL-10的表达与分泌水平。本研究结论为，辐射应激诱导的HERV表达可增强I型干扰素与细胞因子应答，使促炎调节因子水平升高，并伴随与巨噬细胞致瘤表型相关的抗炎因子表达上调。