Effects of interleukin-1 receptor antagonist overexpression in a mouse model of tauopathy.

In vitro, IL-1RA protein was secreted into the cell culture media. IL-1 reporter cell lines transfected with IL-1RA greatly reduced reporter expression in response to IL-1 exposure, indicating the gene product had antagonist activity. Studies in Tg4510 mice detected increases in IL-1 RNA at 6 and 8 mo of age, but not at 4 mo. Measures of IL-1RA by ELISA indicated an over 100 fold increased expression in mice injected with AAV-IL-1RA. However, the only significant impact of IL-1RA expression on tauopathy was a slight reduction in the ELISA values for detergent insoluble p-Ser199-tau in the IL-1RA mice. No differences were found in any of the histological measures of tauopathy or ELISA measures of total tau or p-Ser-396tau CONCLUSION: IL-1RA had a minimal impact on the accumulation of tauopathy in the Tg4510 mice. The overexpression of IL-1RA preceded the endogenous increase in IL-1 in this model. Other studies have found that blocking IL-1 production through inflammasome deletion did reduce tauopathy (Ising et al, Nature (2019) 575:669). These authors used a different mouse model with lower overall expression of tau. The minimal effect seen in this study may relate to the model of tauopathy used, the extent of IL-1 signaling reduction, or the possibility that the effects of inflammasome deletion are mediated through effector molecules other than the IL-1 receptor.