Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects?

Abstract

Haemopoietic tissues exposed to ionizing radiation are shown to exhibit increased macrophage activation, de®ned by ultrastructural characteristics and increased lysosomal and nitric oxide synthase enzyme activities. Macrophage activation post-irradiation was also associated with enhanced respiratory burst activities and an unexpected neutrophil in®ltration. Examination of p53-null mice demonstrated that macrophage activation and neutrophil in®ltration were not direct e ects of irradiation, but were a consequence of the recognition and clearance of radiation-induced apoptotic cells. Increased phagocytic cell activity was maintained after apoptotic bodies had been removed. These ®ndings demonstrate that, contrary to expectation, recognition and clearance of apoptotic cells after exposure to radiation produces both a persistent macrophage activation and an in¯am-matory-type response. We also demonstrate a complexity of macrophage activation following radiation that is genotype dependent, indicating that the in vivo macrophage responses to radiation damage are genetically modi®ed processes. These short-term responses of macrophages to radiation-induced apoptosis and their genetic modi®cation are likely to be important determinants of the longer-term consequences of radiation exposure. Furthermore, in addition to any e ects attributable to immediate radiation-induced damage, our ®ndings provide a mechanism for the production of damage via a`bystander' e ect which may contribute to radiation-induced genomic instability and leukaemogenesis. Oncogene (2001) 20, 7085 ± 7095.

Transient inflammatory response induced by apoptotic cells is an important mediator of melanoma cell engraftment and growth

“…Transient neutrophil infiltration and MIP-2 mRNA expression in the thymus have been observed after X-ray irradiation-induced apoptosis of thymic cells. 29 Lorimore et al 30 have shown that irradiation-induced apoptosis can stimulate proinflammatory responses by splenic macrophages, apparently by directing the ingestion of intact apoptotic cells. Consistent with the neutrophil infiltration observed in this work, there are reports that dying cells can trigger rapid release from macrophages of the neutrophil chemoattractant IL-8 (CXCL8) 31 and Fas ligand (CD95L).…”

From regulation of dying cell engulfment to development of anti-cancer therapy

“…75,79 These discrepancies may be explained by the activation or differentiation state of macrophages (discussed above), the source and activation state of target cells, the type of cell death stimuli, and the presence of TLR ligands resulting in differential recognition mechanisms and immunological consequences. Some bridging molecules, such as surfactant proteins A and D, have a dual function depending on binding orientation and on the receptor system that is triggered.…”

Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

“…Lorimore and Wright (2003) have pointed out that intercellular signaling, production of cytokines and free radicals are features of inflammatory responses and have the potential for both bystander-mediated and persistent damage. Furthermore, they have in vivo evidence for inflammatory-type responses occurring in mice after irradiation (Lorimore et al, 2001). A hypothetical model unifying these features to explain dynamic radiation-induced genomic instability is proposed in Figure 6.…”