Prevention of radiotherapy-induced arterial inflammation by interleukin-1 blockade

Abstract

Aims Radiotherapy-induced cardiovascular disease is an emerging problem in a growing population of cancer survivors where traditional treatments, such as anti-platelet and lipid-lowering drugs, have limited benefits. The aim of the study was to investigate vascular inflammatory patterns in human cancer survivors, replicate the findings in an animal model, and evaluate whether interleukin-1 (IL-1) inhibition could be a potential treatment. Methods and results Irradiated human arterial biopsies were collected during microvascular autologous free tissue transfer for cancer reconstruction and compared with non-irradiated arteries from the same patient. A mouse model was used to study the effects of the IL-1 receptor antagonist, anakinra, on localized radiation-induced vascular inflammation. We observed significant induction of genes associated with inflammasome biology in whole transcriptome analysis of irradiated arteries, a finding supported by elevated protein levels in irradiated arteries of both, pro-caspase and caspase-1. mRNA levels of inflammasome associated chemokines CCL2, CCL5 together with the adhesion molecule VCAM1, were elevated in human irradiated arteries as was the number of infiltrating macrophages. A similar pattern was reproduced in Apoe−/− mouse 10 weeks after localized chest irradiation with 14 Gy. Treatment with anakinra in irradiated mice significantly reduced Ccl2 and Ccl5 mRNA levels and expression of I-Ab. Conclusion Anakinra, administered directly after radiation exposure for 2 weeks, ameliorated radiation induced sustained expression of inflammatory mediators in mice. Further studies are needed to evaluate IL-1 blockade as a treatment of radiotherapy-induced vascular disease in a clinical setting.

Neural reflex control of vascular inflammation

“…Interestingly, in experimental radiation-induced arterial damage, treatment with anti-IL-1β antibodies, i.e. anakinra, significantly reduced inflammation (Christersdottir et al 2019). These findings suggest that anti-cytokine therapy, e.g.…”

Mechanism of Dayuanyin in the treatment of coronavirus disease 2019 based on network pharmacology and molecular docking

“…ILIB has analgesic, immunomodulatory, anti-hypoxia, and anti-inflammatory functions. CCL2 is an important inflammasome-associated chemokine [30]. Inhibition of CCL2 can reduce the infiltration of peripheral inflammatory cells such as monocytes and neutrophils [9].…”

The Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury

“…Additionally, it seems to be rational to start with an early and short-term IL-1β blockage treatment directly after radiotherapy exposure. It is based on the concept that the intervention might not work effectively in already established RIHD, where the chronic inflammatory response is advanced (Christersdottir et al, 2019). Further studies are required to evaluate the optimal timing and treatment-duration of NLRP3 inflammasome signaling inhibition to prevent RIHD.…”

“…A recent gene expression analysis of both irradiated and non-irradiated human blood vessels from the Biobank of Radiated Tissues at Karolinska (BiRKa) was conducted, suggesting the involvement of NLRP3inflammasome and potential treatment using IL-1 inhibitors. According to their findings, treatment with anakinra in irradiated Apoe −/− mice significantly alleviated arterial inflammation (Christersdottir et al, 2019).…”

“…A markedly increased IL-1 expression was observed in irradiated human arteries and veins when compared to non-irradiated (Christersdottir Bjorklund et al, 2013). Increased level of pro-caspase-1 and caspase 1 in human arteries with chronic radiation injury indicated the involvement of NLRP3 inflammasome in RIHD (Christersdottir et al, 2019). However, the outcomes of vascular damage at organ subsites have not been fully characterized, for example, the underlying mechanisms of NLRP3 in radiationinduced CVDs have not yet been established.…”