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. Paired-end stranded RNA-Seq was performed on 14 human samples for a target depth of >=40M read pairs per sample. Of these samples, four represented primary human monocyte-derived macrophages under no ionizing radiation exposure (MDM 0Gy), four represented primary human monocyte-derived macrophages under ionizing radiation exposure (MDM 5Gy), three represented a THP1 monocytic cell line under no ionizing radiation exposure (THP1 0Gy), and three represented a THP1 monocytic cell line under ionizing radiation exposure (THP1 5Gy).