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

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2018

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Şanlı, Hatice Asena

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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.

Subject Keywords

Interferon., Sting (Anatomy), Immunity., Cellular immunity.

URI

http://etd.lib.metu.edu.tr/upload/12622420/index.pdf
https://hdl.handle.net/11511/27437

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Graduate School of Natural and Applied Sciences, Thesis

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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.