Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury

Abstract

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit.

Fig. 1.. Deletion of inflammasome components Aim2 and Nlrp3 do not protect against ARS.

The following animals were subjected to total-body irradiation (TBI): WT (not littermates of the next two groups), Aim2^+/− and Aim2^−/− littermate males (panel A) and females (panel B) at 8.0 or 8.2 Gy TBI (panels C and D); WT (not littermates), Nlrp3^+/− and Nlrp3^−/− littermate males (panel E) and females (panel F) at 8.0 or 8.2 Gy TBI (panels G and H). Mice were monitored for 30 days post irradiation. Survival distributions were estimated using the Kaplan Meier method where differences were examined using the log-rank (Mantel-Cox) test based on the corresponding asymptotic P value, employing a two-sided unadjusted significance level of 0.05. Multiple replicate studies with age- and sex-matched mice were combined with total animals (n) and 30-day survivors per total animals tested indicated within survival plots.

Fig. 2.. Deletion of inflammasome components caspase-1/11 and Asc do not protect against ARS.

The following animals were subjected to TBI: Casp1/11^+/− vs. Casp1/11^−/− littermate males (panel A) or females (panel B) at 8.2 Gy TBI; WT (not littermates of the next two groups), Asc^+/− vs. Asc^−/− littermate males (panel C) or females (panel D) at 7.5 Gy TBI. Mice were monitored for 30 days post irradiation. Survival distributions were estimated using the Kaplan Meier method where differences were examined using the log-rank (Mantel-Cox) test based on the corresponding asymptotic P value, employing a two-sided unadjusted significance level of 0.05. Multiple replicate studies with age- and sex-matched mice were combined with total animals (n) and 30-day survivors per total animals tested indicated within survival plots.