Endocytic cellular components determine secreta in female irradiated macrophages to promote intestinal regeneration

Abstract

Background: The intestine is sensitive to radiation. After irradiation, the DNA of intestinal cells breaks and leaks, resulting in collagen deposition. Macrophages in the intestine perform cleaning and repair functions. However, the specific mechanism between cleaning and repairhas not yet been clarified. Methods and Results: Here, we found that after macrophages engulf DNA, the signal is transmitted to the CCAAT/enhancer binding protein beta (CEBPB) nuclear transcription factor through DEAD-box helicase 5 (DDX5) found by a coimmunoprecipitation assay. Next, a chromatinimmunoprecipitation assay showed that CEBPB bound to the promoter of the bone morphogenetic protein (BMP) inhibitory molecule Gremlin2 (GREM2) to increase GREM2 mRNA. Simultaneously, macrophages swallow collagen, and collagen inhibits HSP90AB1 (heat shock protein 90 kDa alphaB1) and CEBPB. Next, CEBPB suppresses the transforming growth factor (TGF) β inhibitory molecules latent transforming growth factor beta binding protein 1 (LTBP1) and decorin (DCN), leading to increased expression of LTBP1 and DCN in irradiated macrophages. In the presence of estrogen and prolactin, the expression of GREM2, LTBP1, and DCN in irradiated macrophages significantly increased. GREM2 dose-dependently promoted crypt proliferation. Therefore, after depleting macrophages, the intestinal damage of female mice was significantly more severe than that of male mice after irradiation. Conclusions: The data here showed that irradiated intestinal macrophages engulfed DNA and secreted GREM2 (positively regulated by CEBPB), while phagocytic collagen stimulated macrophages to secrete LTBP1 and DCN (negatively regulated by CEBPB). Estrogen will greatly amplify this mixed phenotype to promote intestinalrepair post ionizing radiation. These results suggest that there should be differences in the dosage of radiation therapy between male and female cancer patients.