Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation

Neuron. 2017 Dec 20;96(6):1290-1302. Comments from the lab:

Figure 1 is interesting to report that GCV induces anti-inflammatory IFN-beta and CXCL10.

Fig 2 was a good idea, but panels B, C and D are internally inconsistent with a 5 to 20 fold change in expression by GCV itself.

Figures 3-5 are really controls for the proposed mechanism.  It is relatively well known already that  anti-inflammatory IFN-beta and CXCL10 act through the Jak/STAT and STING/NFkb pathways.   Consequentially, there will be, of course, no improvement in EAE (experimental autoimmune encephalomyelitis, a Multiple Sclerosis model) if these signalling pathways are inactivated. Not clear how this proves that GCV acts directly through IFN-beta or CXCL10.

Figure 7, etc. for disease-associate gene regulation by GCV do not report if the same genes are also similarly regulated by the FDA approved IFN-beta.

In Results: Analogs of GCV were tested only for induction of CXCL10, but not for IFN-beta.

It is not clear what advantage (theoretical or clinical) would be had from using GCV, and not just FDA approved IFN-beta, or CXCL10. Importantly, at low levels GCV is known to induce senescence (Cell Death Dis. 18;4:e727. 2013.199. Mitochondrial DNA damage induces apoptosis in senescent cells.), so the overall beneficial effects or mechanisms of action of GCV in brain remain unclear.