ESTRO 2024 - Abstract Book

S5261

Radiobiology - Normal tissue radiobiology

ESTRO 2024

enrichment in inflammatory responses. In Atf4 Δ/Δ hearts, a notably lower inflammatory profile and the upregulation of pathways related to extracellular matrix degradation were observed. We identified significant enrichment of the IL-10 and IL-4/IL-13 signaling pathways in Atf4 wt/wt - treated relative to Atf4 Δ/Δ -treated hearts. Preliminary data from the multiplex cytokine assay and IF staining indicate that ATF4 can regulate the polarization of M2 macrophages via modulation of the IL-4/STAT6. We have also observed substantially lower TGF-β1 levels in irradiated hearts from Atf4 wt/wt mice, supporting the notion of a less-fibrotic environment in ATF4-deficient mice after RT. This increase has also positively correlated with the transformation of cardiac fibroblasts to myofibroblasts as evidenced by significantly higher expression of ɑ SMA and PDGFR ɑ . Conversely, genetic suppression of ATF4 resulted in a significant reduction in perivascular fibrosis in Atf4 Δ/Δ mice compared with that in Atf4 wt/wt mice at 8 weeks after RT. Furthermore, at 8 weeks post-RT, several parameters, such as the early-to-late (atrial) mitral inflow ratio, were maintained in Atf4 Δ/Δ mice, whereas cardiac functionality was significantly impaired in Atf4 wt/wt mice. In summary, our preliminary data indicates that focal radiation to the cardiac apex upregulates ATF4 in damaged tissue, inducing high levels of IL-4 and promoting the M2 polarization of macrophages, possibly through the IL-4/STAT6 signaling pathway. ATF4 ablation resulted in significant reductions in the levels of inflammatory and profibrotic markers and perivascular fibrosis, with the maintenance of cardiac functionality. Overall, we believe that inhibiting ATF4 can mitigate the onset and progression of RIMF without causing significant toxicity. Conclusion:

Keywords: RIMF, Integrated Stress Response, macrophages

References:

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