Characterization of STING mediated innate immune sensing in the context of pathology

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2018
Şanlı, Hatice Asena
Type I interferonopathies are a group of diseases characterized by excess type I interferon production. Here, we examined the intracellular signal transduction pathways of two interferonopathies, STING-associated vasculopathy with Onset in Infancy (SAVI) and Aicardi-Goutières syndrome (AGS) using in vitro cell line models. SAVI is characterized by constitutive STING activation. M155V and N154S gain-of-function mutations in STING can cause disease in humans. We expressed the M155V mutant STING in STING-knocked out B16 Blue interferon reporter cell line. The effect of STING in tumor progression was investigated in mice using wild type, STING-/- or STINGM155V expressing B16 melanoma cells, with no significant differences between these groups. Using the STINGM155V expressing cells, we investigated type I IFN secretion profile to delineate the mechanism behind the cold-induced exacerbation of inflammation observed in SAVI patients. Similarly, TREX1 KO THP cells were used as a model of Aicardi-Goutières syndrome. Exposure to cold upregulated both p-STING and total STING levels in B16 cells, which may account for cold-temperature associated increase in inflammation in patients. Next, we analyzed the type I IFN suppressing activity of various inhibitors in our cell-line disease models. Results indicated that TBK1/IKK inhibitors Amlexanox and BX-795 were more effective in controlling chronic type I IFN production than the JAK/STAT inhibitors ruxolitinib and tofacitinib. Finally, we also investigated whether or not cGAS/STING signaling is regulated by circadian rhythms. Preliminary data showed that cGAS/STING-dependent type I IFN production oscillated over time, suggesting that this signaling pathway might indeed be under circadian regulation.
Citation Formats
H. A. Şanlı, “Characterization of STING mediated innate immune sensing in the context of pathology,” M.S. - Master of Science, Middle East Technical University, 2018.