Figure 1.

Mechanisms of IFN-I induction. IFN-I expression can be induced by diverse molecules from pathogens (bacteria or virus) or apoptotic host cells, PAMP and DAMP, respectively. These PAMP/DAMP are mostly nucleic acids (DNA and RNA) and are recognized by different cytosolic or membrane surface sensors. Their stimulation activates intracellular signaling cascades leading to the transcription of IFN-I subtypes. Once released, IFN-I subtypes interact with their receptor IFNAR1/2 that is ubiquitously expressed. Its stimulation induces the activation of TYK2 and JAK1, leading to the phosphorylation and heterodimerization of STAT1 and STAT2 that interact with interferon regulatory factor (IRF) 9. This complex, also known as IFN-stimulated gene factor 3 (ISGF3), then translocates into the nucleus and binds the IFN-I stimulated response element (ISRE) to regulate transcription of over 300 ISG. In interferonopathies such as AGS, genes involved in the metabolism of nucleic acids are mutated. This leads to the accumulation of endogenous nucleic acids and the abnormal stimulation of sensors triggering IFN-I expression and leading to the initiation and perpetuation of chronic inflammation.